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Yi Zheng, PhD Director, Experimental Hematology and Cancer Biology
Director, Experimental Hematology and Cancer Biology
Katherine Stewart Waters Endowed Chair
Co-Director, Cancer and Blood Diseases Institute
Professor, UC Department of Pediatrics
Using transgenic and gene targeted mouse models to study the physiological and pathological roles of Rho GTPases and their regulators in hematopoiesis, neurogenesis, lung cancer development and small intestinal stem cell regulations mechanism based, rational design of small molecule inhibitors targeting Rho GTPase signaling modules and pathologic functions in cancer and blood diseases; mouse model studies of mTor signaling function in hematopoietic stem cells and small intestinal stem cells.
Visit the Zheng Lab.
BS: Tsinghua University, Beijing, China, 1986.
MS: Cornell University, Ithaca, NY, 1988.
PhD: Cornell University, Ithaca, NY, 1991.
Postdoctoral Fellow: Cornell University, Ithaca, NY, 1995.
Kesarwani M, Huber E, Kincaid Z, Evelyn CR, Biesiada J, Rance M, Thapa MB, Shah NP, Meller J, Zheng Y, Azam M. Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance. Sci Report. 2015. In press.
Konstantinidis DG, Giger KM, Risinger M, Pushkaran S, Zhou P, Dexheimer P, Yerneni S, Andreassen P, Klingmüller U, Palis J, Zheng Y, Kalfa TA. Cytokinesis failure in RhoA-deficient mouse erythroblasts involves actomyosin and midbody dysregulation and triggers p53 activation. Blood. 2015 Jul 30. [Epub ahead of print]
Barry DM, Xu K, Meadows SM, Zheng Y, Norden PR, Davis GE, Cleaver O. Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation. Development. 2015 Aug 7. [Epub ahead of print]
Yang JQ, Kalim KW, Li Y, Zhang S, Hinge A, Filippi MD, Zheng Y, Guo F. RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation. J Allergy Clin Immunol. 2015 Jun 19. [Epub ahead of print]
Lin Y, Zheng Y. Approaches for targeting Rho GTPases in cancer drug discovery. Expert Opin Drug Discov. 2015 Sep;10(9):991-1010.
Zandvakili I, Davis AK, Hu G, Zheng Y. Loss of RhoA exacerbates, rather than dampens, oncogenic K-Ras induced lung adenoma formation in mice. PLoS One. 2015 Jun 1;10(6):e0127923.
Evelyn CR, Biesiada J, Duan X, Tang H, Shang X, Nelson S, Seibel WL, Meller J, Zheng Y. Combined rational design and a high throughput screening platform for identifying chemical inhibitors of a Ras-activating enzyme. J Biol Chem. 2015 May 15;290(20):12879-98.
Mikelis CM, Simaan M, Ando K, Fukuhara S, Sakurai A, Amornphimoltham P, Masedunskas A, Weigert R, Chavakis T, Adams RH, Offermanns S, Mochizuki N, Zheng Y, Gutkind JS. RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock. Nat Commun. 2015 Apr 10;6:6725.
Li J, Zhang L, Chen Z, Xie M, Huang L, Xue J, Liu Y, Liu N, Guo F, Zheng Y, Kong J, Zhang L. Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen. Neurobiol Dis. 2015 Mar;75:159-76.
Chang KH, Nayak RC, Roy S, Perumbeti A, Wellendorf AM, Bezold KY, Pirman M, Hill SE, Starnes J, Loberg A, Zhou X, Inagami T, Zheng Y, Malik P, Cancelas JA. Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial AT₂R and cytoskeletal dysregulation. Nat Commun. 2015 Jan 9;6:5914.
Cincinnati Center of Excellence in Molecular Hematology. Principal investigator. National Institutes of Health. Sep 2010–June 2016. NIH P30 DK090971 S2.
Lineage Determination and Tissue Homeostasis in the aged Hematopoietic System. Principal investigator. National Institutes of Health. Aug 2011–July 2016. NIH R01AG040118.
Rho GTPase inhibitors for refrigerated platelet storage. Co-principal investigator. National Institutes of Health. Aug 2014–July 2016. NIH R43HL123103.
Targeting Cdc42 for bone marrow transplant therapies. Principal investigator. National Institutes of Health. April 2015—April 2020. NIH R01CA193350.
Stem cell aging and biomarker studies. Principal investigator. National Institutes of Health. Sep 2015—Aug 2016. NIH R56 AG050650.
Paul R. Andreassen, PhD Member, Division of Experimental Hematology & Cancer Biology
Member, Division of Experimental Hematology & Cancer Biology
Associate Professor, UC Department of Pediatrics
Fanconi anemia; cell cycle check points; genetic instability; replication stress; relationship of DNA repair and chromatin; mitosis; cell biology
BS: Willamette University, Salem, Oregon, 1984.
PhD: University of Washington, Seattle, Washington, 1995.
Park JY, Singh TR, Nassar N, Zhang F, Freund M, Hanenberg H, Meetei AR, Andreassen PR. Breast
cancer-associated missense mutants of the PALB2 WD40 domain, which
directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair. Oncogene. 2014 Oct 2;33(40):4803-12.
Duan W, Gao L, Zhao W, Leon M, Sadee W, Webb A, Resnick K, Wu X, Ramaswamy B, Cohn DE, Shapiro C, Andreassen PR, Otterson GA, Villalona-Calero MA. Assessment of FANCD2 nuclear foci formation in paraffin-embedded tumors: a potential patient-enrichment strategy for treatment with DNA interstrand crosslinking agents. Trans Res. 2013; 161(3): 156-64.
Du W, Rani R, Sipple J, Schick J, Myers KC, Mehta P, Andreassen PR, Davies SM, Pang Q. The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters. Blood. 2012;119(18): 4142-51.
Sin HS, Barski A, Zhang F, Kartashov AV, Nussenzweig A, Chen J, Andreassen PR, Namekawa SH. RNF8 regulates active epigenetic modifications and escape gene activation from inactive sex chromosomes in post-meiotic spermatids. Genes Dev. 2012 26(24):2737-48.
Zhang F, Bick G, Park JY, Andreassen PR. MDC1 and RNF8 function in a pathway that directs BRCA1-dependent localization of PALB2 required for homologous recombination. J Cell Sci. 2012; 125(24):6049-57.
Ichijima Y, Ichijima M, Lou Z, Nussenzweig A, Camerini-Otero RD, Chen J, Andreassen PR and Namekawa SH. MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells. Genes Dev. 2011;25(9):959-71.
Kavanaugh GM, Wise-Draper TM, Morreale RJ, Morrison MA, Gole B, Schwemberger S, Tichy ED, Lu L, Babcock GF, Wells JM, Drissi R, Bissler JJ, Stambrook PJ, Andreassen PR, Wiesmuller L and Wells SI. The human DEK oncogene regulates DNA damage response signaling and repair. Nucleic Acids Res. 2011 ;39(17):7465-76.
Melendez J, Stengel K, Zhou X, Chauchan BK, Debidda M, Andreassen PR, Lang RA and Zheng Y. RhoA GTPase is dispensable for actomyosin regulation but is essential for mitosis in primary mouse embryonic fibroblasts. J Biol Chem. 2011;286(17):15132-7.
Montes de Oca R, Andreassen PR and Wilson KL. Barrier-to-autointegration factor influences specific histone modifications. Nucleus. 2011; 2(6):580-90.
Hayakawa T, Zhang F, Hayakawa N, Ohtani Y, Shinmyozu K, Nakayama J and Andreassen PR. MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks. J Cell Sci. 2010;127(Pt 7):1124-30.
Zhang F, Fan Q, Ren K, Auerbach AD and Andreassen PR. FANCJ/BRIP1 recruitment and regulation of FANCD2 in DNA damage responses. Chromosoma. 2010;119(6):637-49.
Pang Q and Andreassen PR. Fanconi anemia proteins and endogenous stresses. Mutat Res. 2009;668(1-2):42-53.
Fan Q, Zhang F, Barrett B, Ren K and Andreassen PR. A role for monoubiquitinated FANCD2 at telomeres in ALT cells. Nucleic Acids Res. 2009;37(6):1740-54.
Andreassen PR and Ren K. Fanconi anemia proteins, DNA interstrand crosslink repair pathways, and cancer therapy. Curr. Cancer Drug Targets. 2009;9(1):101-17.
Zhang F, Fan Q, Ren K and Andreassen PR. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol Cancer Res. 2009;7(7):1110-8.
Mohammad Azam, PhD Member, Division of Experimental Hematology & Cancer Biology
is interested in understanding molecular basis of human cancers, especially hematopoietic malignancies. His research group focuses on understanding the mechanisms of tyrosine kinase regulation, oncogene addiction and the development of cancer stem cells.
Assistant Professor, UC Department of Pediatrics
Azam M, Powers JT, Einhorn W, Huang WS, Shakespeare WC, Zhu X, Dalgarno D, Clackson T, Sawyer TK, Daley GQ. AP24163 inhibits the gatekeeper mutant of BCR-ABL and suppresses in vitro resistance. Chem Biol Drug Des. 2010 Feb;75(2):223-7.
Zhang J, Adrián FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010 Jan 28;463(7280):501-6.
Nardi V, Azam M, Neverias O, Daley GQ. Immune-Mediated Protection Against BCR/ABL-Induced Leukemia: A Common Pathway Shared between IRF8/ICSBP and IFN alpha and beta. Blood. 2009.
Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, O'Sullivan M, Lu J, Phillips LA, Lockhart VL, Shah SP, Tanwar PS, Mermel CH, Beroukhim R, Azam M, Teixeira J, Meyerson M, Hughes TP, Llovet JM, Radich J, Mullighan CG, Golub TR, Sorensen PH, Daley GQ. Lin28 promotes transformation and is associated with advanced human malignancies. Nature Genetics. 2009 Jul;41(7):843-8.
Azam M, Seeliger M, Gray S, Kuriyan J, Daley GQ. Activation of tyrosine kinases by the mutation of gatekeeper residue. Nat Struct Mol Biol. 2008 Oct;15(10):1109-18.
Raz T, Nardi V, Azam M, Cortes J, Daley GQ. Farnesyl transferase inhibitor resistance probed by target mutagenesis. Blood. 2007 Sep 15;110(6):2102-9.
Azam M, Nardi V, Shakespeare WC, Metcalf CA 3rd, Bohacek RS, Wang Y, Sundaramoorthi R, Sliz P, Veach DR, Bornmann WG, Clarkson B, Dalgarno DC, Sawyer TK, Daley GQ. Activity of dual SRC-ABL inhibitors highlights role of BCR/ABL kinase dynamics in drug resistance. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9244-9.
Azam M, and Daley GQ. Anticipating Clinical Resistance to Target-directed Agents: BCR-ABL an example. Molecular Diagnosis and Therapy. 2006;10(2):67-76.
Elisa Boscolo, PhD
Elisa Boscolo received her PhD from the University of Padua, Italy. She completed her postdoctoral training and worked as instructor in Joyce Bischoff's laboratory where she investigated the cellular basis and the molecular signaling involved in infantile hemangioma formation. In May 2014, Dr. Boscolo moved to Cincinnati Children’s Hospital Medical Center to study vascular anomalies.
BS: Molecular Biology, University of Padua, Padova, Italy.
PhD: Tissue Engineering, University of Padua, Padova, Italy.
Postdoctoral Fellowship: Vascular Biology, Boston Children’s Hospital, Harvard Medical School, Cambridge, MA.
Boscolo E, Limaye N, Huang L, Kang KT, Soblet J, Uebelhoer M, Mendola A, Natynki M, Seront E, Dupont S, Hammer J, Legrand C, Brugnara C, Eklund L, Vikkula M, Bischoff J, Boon LM. Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J Clin Invest. 2015 Aug 10.
Boscolo E, Coma S, Luks VL, Greene AK, Klagsbrun M, Warman ML, Bischoff J. AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation. Angiogenesis. 2014 Nov 26.
Lee D, Boscolo E, Durham JT, Mulliken JB, Herman IM, Bischoff J. Propranolol Targets Contractility of Infantile Hemangioma-derived Pericytes. Br J Dermatol. 2014 Nov;171(5):1129-37.
Smadja DM, Guerin CL, Boscolo E, Bieche I, Mulliken JB, Bischoff J. α6-integrin is required for the adhesion and vasculogenic potential of hemangioma stem cells. Stem Cells. 2014; 32(3):684-93.
Boscolo E, Mulliken JB, Bischoff J. Pericytes from Infantile Hemangioma Display Pro-angiogenic Properties and Dysregulated Angiopoietin-1. Arterioscler Thromb Vasc Biol. 2013 Mar;33(3):501-9.
Stahl A, Joyal JS, Chen J, Sapieha P, Juan AM, Hatton CJ, Pei DT, Hurst CG, Seaward MR, Krah NM, Dennison RJ, Greene ER, Boscolo E, Panigrahy D, Smith LE. SOCS3 is an endogenous Inhibitor of pathologic angiogenesis. Blood. 2012; 120(14):2925-9.
Boscolo E, Mulliken JB, Bischoff J. VEGFR-1 mediates endothelial differentiation and formation of blood vessels in a murine model of infantile hemangioma. Am J Pathol. 2011 Nov;179(5):2266-77.
Greenberger S, Yuan S, Walsh LA, Boscolo E, Kang KT, Matthews B, Mulliken JB, Bischoff J. Rapamycin Suppresses Self-Renewal and Vasculogenic Potential of Stem Cells Isolated from Infantile Hemangioma. J Invest Dermatol. 2011 Dec;131(12):2467-76.
Boscolo E, Stewart CL, Greenberger S, Wu JK, Durham JT, Herman IM, Mulliken JB, Kitajewski J, Bischoff J. JAGGED1 Signaling Regulates Hemangioma Stem Cell-to-Pericyte/Vascular Smooth Muscle Cell Differentiation. Arterioscler Thromb Vasc Biol. 2011 Oct; 31(10):2181-92.
Greenberger S, Boscolo E, Adini I, Mulliken JB, Bischoff J. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med. 2010 Mar 18;362(11):1005-13.
Jose A. Cancelas Perez, MD, PhD Division Director of Research, Hoxworth Blood Center
Division Director of Research, Hoxworth Blood Center
Deputy Director, Hoxworth Blood Center
Director, Research Flow Cytometry Core
Leader, Stem Cell Program
Medical Director of Cellular Therapies, Hoxworth Blood Center
Hematopoietic stem cell proliferation and differentiation
MD: Autonomous University of Madrid, Spain, 1989.
Residency: Hematology and Hematotherapy, University of Alcala de Henares, Madrid, Spain, 1993.
PhD: Faculty of Medicine, University of Alcala de Henares, Madrid, Spain, 1996.
Dumont LJ*, Cancelas JA*, Graminske S, Friedman KD, Vassallo RR, Whitley PH, Rugg N, Dumont DF, Herschel L, Siegal AH, Szczepiorkowski ZM, Fender L, Razatos A. In vitro and in vivo quality of leukocyte-reduced apheresis platelets stored in a new platelet additive solution. Transfusion. 2012. (*both authors contributed equally).
Prada CE, Jousma E, Rizvi TA, Wu J, Dunn RS, Mayes DA, Cancelas JA, Dombi E, Kim MO, West BL, Bollag G, Ratner N. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 2013 Jan;125(1):159-68.
Dumont LJ, Cancelas J, Dumont DF, Siegel AH, Szczepiorkowski ZM, Rugg R, Pratt PG, Worsham DN, Hartman EL, Dunn SK, O’Leary M, Ransom JH, Michael RA, Macdonald VW. A randomized controlled trial evaluating recovery and survival of 6% dimethyl sulfoxide-frozen autologous platelets in healthy volunteers. Transfusion. 2013 Jan;53(1):128-37.
Taniguchi Ishikawa E, Cancelas JA. Lack of communication rusts and ages stem cells. Cell Cycle. 2012 Sep 1;11(17):3149-3150.
Geiger H, Pawar SA, Kerschen EJ, Nattamai KJ, Hernandez I, Liang HP, Fernández JA, Cancelas JA, Ryan MA, Kustikova O, Schambach A, Fu Q, Wang J, Fink LM, Petersen KU, Zhou D, Griffin JH, Baum C, Weiler H, Hauer-Jensen M. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat Med. 2012 Jul;18(7):1123-9.
Chang KH, Sanchez-Aguilera A, Shen S, Sengupta A, Madhu MN, Ficker AM, Dunn SK, Kuenzi AM, Anrett JL, Santho RA, Agirre X, Perentesis JP, Deininger MW, Zheng Y, Bustelo XR, Williams DA, Cancelas JA. Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation and survival. Blood. 2012 Jul 26;120(4):800-11.
Taniguchi Ishikawa E, Gonzalez-Nieto D, Ghiaur G, Dunn SK, Ficker AM, Murali B, Madhu M, Gutstein DE, Fishman GI, Barrio LC, Cancelas JA. Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc Natl Acad Sci USA. 2012 Jun 5;109(23):9071-6.
Konstantinidis DG, Pushkaran S, Johnson JF, Cancelas JA, Manganaris S, Harris CE, Williams DA, Zheng Y, Kalfa TA. Signaling and cytoskeletal requirements in erythroblast enucleation. Blood. 2012 Jun 21;119(25):6118-27.
Gonzalez-Nieto D, Li L, Köhler A, Ghiaur G, Ishikawa E, Sengupta A, Madhu M, Arnett J, Santho R, Dunn S, Fishman G, Gutstein D, Civitelli R, Barrio L, Gunzer M, Cancelas J. Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood. 2012 May 31;119(22):5144-54.
Sengupta A, Ficker A, Dunn S, Madhu M, Cancelas JA. Bmi1 reprograms chronic myelogenous leukemia B-lymphoid progenitors to become B-ALL-initiating cells. Blood. 2012 Jan 12;119(2):494-502.
Lionel M.L. Chow, MD, PhD St. Baldrick’s Foundation Scholar
St. Baldrick’s Foundation Scholar
Sontag Foundation Distinguished Scientist
Lionel Chow, MD, PhD, received his medical and graduate degrees from McGill University in Montreal, Canada, where his research focused on the regulation of T-lymphocyte signaling by the intracellular tyrosine protein kinases Lck and Csk.
Following his clinical training in pediatrics and pediatric hematology / oncology at the Hospital for Sick Children in Toronto, Canada, he moved to St. Jude Children’s Research Hospital in Memphis, Tenn., to pursue his research interests.
Chow's research interests have been centered on glioblastoma multiforme, a particularly devastating form of cancer in adults and children. His work has resulted in the development of a number of novel and robust laboratory models for this disease. Using these models and interfacing with clinical trials in the Neuro-Oncology Program as well as those from national consortia such as the Children's Oncology Group (COG) and the Pediatric Brain Tumor Consortium (PBTC), Chow’s laboratory will continue research in this area with the goals of better understanding the origins of this form of cancer and improving patient outcomes.
PhD: McGill University, Montreal, Quebec, Canada, 1996.
MDCM: McGill University, Montreal, Quebec, Canada, 1997.
Residency: The Hospital for Sick Children, University of Toronto, Toronto, Canada, 1997-2000.
Clinical Fellowship: The Hospital for Sick Children, University of Toronto, Toronto, Canada, 2000-2003.
Postdoctoral Fellowship: St. Jude Children’s Research Hospital, Memphis, TN, 2003-2009.
Clinical Fellowship: St. Jude Children’s Research Hospital, Memphis TN, 2008-2009.
Certification: Pediatrics, 2000.
Hummel, TR, Chow, LML, Fouladi, M, and Franz, D. Pharmacotherapeutic management of pediatric astrocytomas: current and upcoming strategies. Pediatric Drugs 2013; 15:29-42.
Joshi, K, Banasavadi-Siddegowda, Y, Mo, X, Kim, SH, Mao, P, Kig, C, Nardini, D, Sobol, RW, Chow, LML, Kornblum, HI, Waclaw, R, Beullens, M, and Nakano, I. MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Stem Cells 2013; 31:1051-1063.
Zhong, Y, Wan, Y-W, Pang, K, Chow, LML, and Liu, Z. Digital sorting of complex tissues for cell type-specific gene expression profiles. BMC Bioinformatics 2013; 14:89.
Rafalski, VA, Ho, PP, Brett, JO, Ucar, D, Dugas, JC, Pollina, EA, Chow, LML, Ibrahim, A, Baker, SJ, Barres, BA, Steinman, L, and Brunet, A. Expansion of oligodendrocyte progenitor cells upon SIRT1 inactivation in the adult brain. Nature Cell Biol. 2013; 15:614-624.
Wojton, J, Chu, Z, Mathsyaraja, H, Meisen, WH, Denton, N, Kwon, C-H, Chow, LML, Palascak, M, Franco, R, Bourdeau, T, Thornton, S, Ostrowski, MC, Kaur, B, and Qi, X. Systemic delivery of SapC-DOPS has antiangiogenic and antitumor effects against glioblastoma. Mol. Ther. 2013; 21:1517-1525.
Chow LML, Endersby R, Zhu X, Rankin S, Qu C, Zhang J, Broniscer A, Ellison DW, Baker SJ. Cooperativity within and among Pten, p53 and Rb pathways induces high-grade astrocytoma in adult brain. Cancer Cell. 2011;19:305-316.
Lavado A, Lagutin O, Chow LML, Baker SJ, Oliver G. Prox1 is required for granule cell maturation and intermediate progenitor maintenance during brain neurogenesis. PLoS Biol. 2010;8:e1000460.
Cicero SA, Johnson D, Reyntjens S, Frase S, Connell S, Chow LML, Baker SJ, Sorrentino BP, Dyer MA. Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells. Proc Natl Acad Sci U S A. 2009 Apr;106(16):6685-90.
Weber T, Corbett MK, Chow LML, Valentine MB, Baker SJ, Zuo J. Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells. Proc Natl Acad Sci U S A. 2008;105(2):781-5.
Chow LML, Zhang J, Baker SJ. Inducible Cre recombinase activity in mouse mature astrocytes and adult neural precursor cells. Transgenic Res. 2008;17(5):919-28.
Biplab Dasgupta, PhD, MS Member, Cancer Biology and Neural Tumors Program
Member, Cancer Biology and Neural Tumors Program
Biplab Dasgupta, PhD, MS, completed his doctorate in molecular biology and immunology at the Indian Institute of Chemical Biology, Calcutta, and a postdoctoral fellowship at Washington University School of Medicine, Saint Louis. Dr. Dasgupta came to Cincinnati Children's Hospital Medical Center in August 2009 as an assistant professor of pediatrics within the University of Cincinnati College of Medicine. He is interested in understanding how neural cell / stem cell metabolic and energy status is linked to cell cycle, lineage commitment, differentiation and tumorigenesis. His other interests include genetic, developmental, post-translational, tissue- and stimuli–specific regulation of the subunits that constitute the AMP kinase complex.
PhD: Indian Institute of Chemical Biology, Calcutta, 2003.
Postdoctoral Fellowship: Washington University School of Medicine, Saint Louis.
Xiaona Liu, Rishi Raj Chhipa and Biplab Dasgupta*. The Selective AMPK inhibitor Compound C is a potent AMPK-independent anti-glioma agent. Mol Cancer Ther. *Corresponding author. 2014 Mar:13(3):596-605
Xiaona Liu, Rishi Raj Chhipa, Shabnam Pooya, Matthew Wortman, Sara Yachishin, Ashish Kumar, Lionel Chow, Xuan Zhou, Ying Sun, Brian Quinn, Christopher McPherson, Ronald Warnick, Adi Kendler, Sailendra Giri, Jeroen Poels, Koennard Nogra, Benoit Viollet, Gregory A. Grabowski and Biplab Dasgupta*. Novel mechanisms of mTOR and cdc25c regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sc U S A. *Corresponding author. 2014 Jan 28;111(4):E435-44.
Karkare S, Chhipa RR, Anderson J, Liu X, Henry H, Gasilina A, Nassar N, Roychoudhury J, Clark JP, Kumar A, Pauletti GM, Ghosh PK, Dasgupta B*. Direct inhibition of Retinoblastoma phosphorylation by Nimbolide causes cell cycle arrest and suppresses glioblastoma growth. Clin Cancer Research. 2014 Jan 1:20(1):199-212.
Dasgupta B, Ju JS, Sasaki Y, Liu X, Jung SR, Higashida K, Lindquist D, Milbrandt J. The AMPK beta2 subunit is required for energy homeostasis during metabolic stress. Mol Cell Biol. 2012; 32: 2837-48. Cover article. *Corresponding author.
Dasgupta B, Milbrandt J. AMP-activated protein kinase phosphorylates retinoblastoma protein to control mammalian brain development. Dev Cell. 2009 Feb;16(2):256-70.
Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 2007 Apr;24;104(17):7217-22.
Hegedus B, Dasgupta B, Shin JE, Emnett RJ, Hart-Mahon EK, Elghazi L, Bernal-Mizrachi E, Gutmann DH. Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP- and Ras-dependent mechanisms. Cell Stem Cell. 2007 Oct 11;1(4):443-57.
Dasgupta B, Gutmann DH. Neurofibromin regulates neural stem cell proliferation, survival, and astroglial differentiation in vitro and in vivo. J Neurosci. 2005 Jun 8;25(23):5584-94.
Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 2005 Apr 1;65(7):2755-60.
Dasgupta B, Li W, Perry A, Gutmann DH. Glioma formation in neurofibromatosis 1 reflects preferential activation of K-RAS in astrocytes. Cancer Res. 2005 Jan 1;65(1):236-45.
Marie-Dominique Filippi, PhD
Dr. Filippi is particularly interested in dissecting the molecular mechanism of hematopoietic cell migration, including neutrophils and hematopoietic stem cells in physiological settings. Migration is a critical function of hematopoietic cell in which actin cytoskeleton reorganization plays a central role. Because hematopoietic cells are utilized for the therapy of multiple blood diseases and neutrophils are responsible for maintaining an immunocompetence status, understanding the molecular mechanism of normal hematopoietic cell functions is of potential therapeutic importance. The small RHO GTPase family, members of the Ras superfamily, including Rac, RHO and CDC42, play key roles in regulating many of these functions. During her post-doc in the laboratory of Dr. David Williams, they have demonstrated that two highly related proteins, Rac1 and Rac2, of the small Rho GTPase family, have distinct functions in the control of hematopoietic cell functions. In particular in neutrophils, they have shown that both Rac1 and Rac2 regulate cell migration but with distinct mechanism (Gu and Filippi et al, Science 2003) both in vitro and in vivo. In addition to this work, they have dissected the sequence/determinant specificity of Rac2 versus Rac1 functions in neutrophils and demonstrated that Rac2 controls its functions, at least in part, by distinct subcellular distributions of these GTPases (Tao et al, Blood 2002, Filippi et al, Nat Immunol 2004), highlighting one important mechanism controlling cellular functions.
Dr. Filippi's laboratory, in collaboration Dr. Yi Zheng, is now focused on determining the role of CDC42 and RhoA in neutrophil migration and in determining specifically the role of RhoA in hematopoietic stem cell migration and proliferation using gene targeted knock out mice for CDC42 and RhoA and their respective regulator CDC42GAP and 190RhoGAP. These studies will use in vitro and in vivo assays of cell migration as well as immunofluorescence microscopy to study cytoskeleton rearrangement associated with cell migration.
The long term goal of these studies is to identify new molecular targets of potential therapeutic importance.
Visit the Filippi Lab.
PharmD: University of Rene Descartes, Paris, France, 1998.
Residency: Hematopathology, University of Rene Descartes, Assistance public Hospital of Paris, Paris, France.
Certification: Hematopathology, 2001.
PhD: University of Denis Diderot, Paris, France, 2001.
Mulloy JC, Cancelas JA, Filippi MD, Kalfa TA, Guo F, Zheng Y. Rho GTPases in hematopoiesis and hemopathies. Blood. 2010 Feb 4;115(5):936-47.
Szczur K, Zheng Y, Filippi MD. The small Rho GTPase Cdc42 regulates neutrophil polarity via CD11b integrin signaling. Blood. 2009 Nov 12;114(20):4527-37.
Xu H, Eleswarapu S, Geiger H, Szczur K, Daria D, Zheng Y, Settleman J, Srour EF, Williams DA, Filippi MD. Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential. Blood. 2009 Oct 22;114(17):3557-66.
Gu Y, Harley IT, Henderson LB, Aronow BJ, Vietor I, Huber LA, Harley JB, Kilpatrick JR, Langefeld CD, Williams AH, Jegga AG, Chen J, Wills-Karp M, Arshad SH, Ewart SL, Thio CL, Flick LM, Filippi MD, Grimes HL, Drumm ML, Cutting GR, Knowles MR, Karp CL. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature. 2009 Apr 23;458(7241):1039-42.
Monk KR, Wu J, Williams JP, Finney BA, Fitzgerald ME, Filippi MD, Ratner N. Mast cells can contribute to axon-glial dissociation and fibrosis in peripheral nerve. Neuron Glia Biol. 2007 Aug;3(3):233-44.
Daria D, Filippi MD, Knudsen ES, Faccio R, Li Z, Kalfa T, Geiger H. The retinoblastoma tumor suppressor is a critical intrinsic regulator for hematopoietic stem and progenitor cells under stress. Blood. 2008 Feb 15;111(4):1894-902.
Uchida K, Beck DC, Yamamoto T, Berclaz PY, Abe S, Staudt MK, Carey BC, Filippi MD, Wert SE, Denson LA, Puchalski JT, Hauck DM, Trapnell BC. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med. 2007 Feb 8;356(6):567-79.
Filippi MD, Szczur K, Harris CE, Berclaz PY. Rho GTPase Rac1 is critical for neutrophil migration into the lung. Blood. 2007 Feb 1;109(3):1257-64.
Szczur K, Xu H, Atkinson S, Zheng Y, Filippi MD. Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Blood. 2006 Dec 15;108(13):4205-13.
Wang L, Yang L, Filippi MD, Williams DA, Zheng Y. Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment. Blood. 2006 Jan 1;107(1):98-105.
Matthew J. Flick, PhD
is working to understand how hemostatic factors in the blood that are responsible for clotting also drive inflammation in the context of infection and diseases such as arthritis and fatty liver disease.
Hemostatic factors and arthritis pathogenesis
Research Interests and Focus:
1. Activation of the coagulation system, including the central coagulation protease thrombin, is a prominent feature of both human rheumatoid arthritis and experimental inflammatory arthritis. The long-term goal of Dr. Flick's research program is to determine how thrombin drives inflammatory joint disease. The proposed work will fill significant gaps in the understanding of the interplay between the thrombin- fibrinogen axis and arthritic disease, and may provide the proof-of-principle for the use of novel "customized" thrombin mutants with selected substrate specificity to treat arthritis.
2. The pervasive gram-positive bacteria Staphylococcus aureus is a common pathogen that is the causative agent for a wide spectrum of diseases including skin infections, pneumonia, bacteremia, toxic-shock syndrome and sepsis. Notably, this pathogen has evolved and maintained a number of proteins that directly engage the host hemostatic system, including factors that directly interact with the host coagulation factor fibrinogen. The long-term goal of his research program is to understand how bacterial derived proteins interact with host factors to promote bacterial virulence in the context of blood-born infections. This work will provide novel insight into the molecular pathways by which S. aureus invades and disseminates within host tissues and may shed light into novel strategies for eliminating this potentially devastating infectious agent.
3. Obesity is a worldwide epidemic linked to numerous disease sequelae, including non-alcoholic fatty liver disease (NAFLD). This spectrum disorder can progress from the simple accumulation of triglycerides within hepatocytes (i.e., steatosis), to inflammatory steatohepatitis, to organ failure secondary to irreversible liver fibrosis and cirrhosis. Dysregulation of the coagulation system has been documented in both patients with fatty liver disease and animal models of NAFLD, but any contribution to disease progression has remained largely undefined. Using a murine model of high fat diet (HFD)-induced NAFLD, they are testing the hypothesis that thrombin activity and fibrin deposition drive local inflammatory events promoting the progression of steatosis and steatohepatitis. Comparative studies of wild-type mice with genetically imposed deficiencies or functional alterations in prothrombin, fibrinogen and other associated coagulation factor components suggests that the thrombin-fibrinogen axis influences NAFLD pathogenesis by controlling local inflammatory processes that drive steatosis and by an unanticipated and unknown mechanism tying fibrin(ogen) to HFD-induced weight gain/obesity. Their research has far-reaching implications not only for the treatment and prevention of fatty liver disease, but also for all the downstream sequelae of obesity and even the development of diet-mediated weight gain itself.
BS: Xavier University, Cincinnati, OH.
PhD: Purdue University, West Lafayette, IN.
Post-doctoral Fellow: Cincinnati Children’s Hospital and Medical Center, Division of Developmental Biology, Cincinnati, OH.
Flick MJ, Du X, Prasad JM, Raghu H, Palumbo JS, Smeds E, Höök M, Degen JL. Genetic elimination of the binding motif on fibrinogen for the S. aureus virulence factor ClfA improves host survival in septicemia. Blood. 2013 Jan 8.
Sullivan BP, Kassel KM, Jone A, Flick MJ, Luyendyk JP. Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury. American Journal of Pathology. 2012;180(6):2321-2329.
Qi X, Flick MJ, Frederick M, Chu Z, Mason R, DeLay M, Thornton S. Saposin C Coupled Lipid Nanovesicles Specifically Target Arthritic Mouse Joints for Optical Imaging of Disease Severity. PLoSOne. 2012;7(3):e33966.
Vidal B, Ardite E, Suelves M, Ruiz-Bonilla V, Janué A, Flick MJ, Degen JL, Serrano AL, Muñoz-Cánoves P. Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor. Human Molecular Genetics. 2012;21(9):1989-2004.
Horowitz NA, Blevins EA, Miller WM, Perry AR, Talmage KE, Mullins ES, Flick MJ, Queiroz KC, Shi K, Spek CA, Conway EM, Monia BP, Weiler H, Degen JL, Palumbo JS. Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain. Blood. 2011 Jul 25.
Raghu H, Flick MJ. Targeting the Coagulation Factor Fibrinogen for Arthritis Therapy. Curr Pharm Biotechnol. 2011 Mar 14.
Flick MJ, Chauhan AK, Frederick M, Talmage KE, Kombrinck KW, Miller W, Mullins ES, Palumbo JS, Zheng X, Esmon NL, Esmon CT, Thornton S, Becker A, Pelc LA, Di Cera E, Wagner DD, Degen JL. The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A. Blood. 2011 Jun 9;117(23):6326-37.
Steinbrecher KA, Horowitz NA, Blevins EA, Barney KA, Shaw MA, Harmel-Laws E, Finkelman FD, Flick MJ, Pinkerton MD, Talmage KE, Kombrinck KW, Witte DP, Palumbo JS. Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen. Cancer Res. 2010 Apr 1;70(7):2634-43.
Lykens JE, Terrell CE, Zoller EE, Divanovic S, Trompette A, Karp CL, Aliberti J, Flick MJ, Jordan MB. Mice with a selective impairment of IFN-gamma signaling in macrophage lineage cells demonstrate the critical role of IFN-gamma-activated macrophages for the control of protozoan parasitic infections in vivo. J Immunol. 2010 Jan 15;184(2):877-85.
Mullins ES, Kombrinck KW, Talmage KE, Shaw MA, Witte DP, Ullman JM, Degen SJ, Sun W, Flick MJ, Degen JL. Genetic elimination of prothrombin in adult mice is not compatible with survival and results in spontaneous hemorrhagic events in both heart and brain. Blood. 2009 Jan 15;113(3):696-704.
NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases Research. Director. Cincinnati Rheumatic Diseases Core Center. Aug 2011-Jun 2016. 2P30 AR47363.
Hemostatic factors and sickle cell disease. Co-investigator. NIH. Dec 2011-Nov 2016. R01 HLI12603.
Hartmut Geiger, PhD Director, Mouse Core
Director, Mouse Core
Hematopoietic stem cells; genetics; aging/longevity; plasticity of stem cells; mobilization; DNA-repair.
MS: Studies in chemistry at the University Karlsruhe, Germany and studies in biochemistry at the University Witten/Herdecke, Germany, 1996.
PhD: Max-Planck Institut für Immunbiologie in Freiburg, Germany. Plasticity of murine hematopoietic stem cells, 1999.
Postdoctoral Studies: University of Kentucky, Lexington, USA. Genetic analysis of hematopoiesis and aging/longevity in mice.
Ryan MA, Nattamai KJ, Xing E, Schleimer D, Daria D, Sengupta A, Köhler A, Liu W, Gunzer M, Jansen M, Ratner N, Le Cras TD, Waterstrat A, Van Zant G, Cancelas JA, Zheng Y, Geiger H. Pharmacological inhibition of EGFR signaling enhances G-CSF-induced hematopoietic stem cell mobilization. Nat Med. 2010 Oct;16(10):1141-6.
Kalfa TA, Pushkaran S, Zhang X, Johnson JF, Pan D, Daria D, Geiger H, Cancelas JA, Williams DA, Zheng Y. Rac1 and Rac2 GTPases are necessary for early erythropoietic expansion in the bone marrow but not in the spleen. Haematologica. 2010 Jan;95(1):27-35.
Geiger H, Rudolph KL. Aging in the lymphohematopoietic stem cell compartment. Trends Immunol. 2009 Jul;30(7):360-5. Review.
Geiger H, David S, Nattamai KJ, Jan V. Quantification of genomic mutations in murine hematopoietic cells. Methods Mol Biol. 2009;506:423-36.
Williams JP, Wu J, Johansson G, Rizvi TA, Miller SC, Geiger H, Malik P, Li W, Mukouyama YS, Cancelas JA, Ratner N. Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential. Cell Stem Cell. 2008 Dec 4;3(6):658-69.
Bhatla D, Gerbing RB, Alonzo TA, Conner H, Ross JA, Meshinchi S, Zhai X, Zamzow T, Mehta PA, Geiger H, Perentesis J, Davies SM. Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia. Br J Haematol. 2009 Feb;144(3):388-94.
Milsom MD, Jerabek-Willemsen M, Harris CE, Schambach A, Broun E, Bailey J, Jansen M, Schleimer D, Nattamai K, Wilhelm J, Watson A, Geiger H, Margison GP, Moritz T, Baum C, Thomale J, Williams DA. Reciprocal relationship between O6-methylguanine-DNA methyltransferase P140K expression level and chemoprotection of hematopoietic stem cells. Cancer Res. 2008 Aug 1;68(15):6171-80.
Diwan A, Koesters AG, Capella D, Geiger H, Kalfa TA, Dorn GW 2nd. Targeting erythroblast-specific apoptosis in experimental anemia. Apoptosis. 2008 Aug;13(8):1022-30.
Daria D, Filippi MD, Knudsen ES, Faccio R, Li Z, Kalfa T, Geiger H. The retinoblastoma tumor suppressor is a critical intrinsic regulator for hematopoietic stem and progenitor cells under stress. Blood. 2008 Feb 15;111(4):1894-902.
H. Leighton (Lee) Grimes, PhD Director, Cancer Pathology Program, Division of Experimental Hematology & Division of Pathology
Director, Cancer Pathology Program, Division of Experimental Hematology & Division of Pathology
Co-Leader, Program in Hematologic Malignancies of Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute
Transcriptional control of hematopoiesis and cancer.
Visit the Grimes Lab.
Dr. Grimes has a broad background in hematopoiesis, molecular biology, and molecular oncology including modeling of hematopoiesis, myelopoiesis and leukemia. His work on the Growth factor independent-1 (Gfi1) transcriptional repressor protein has spanned the initial identification of Gfi1 in a model of leukemia and the role of Gfi1 in normal myeloid biology, to the identification of GFI1 mutations in patients with severe congenital neutropenia (SCN) and non-immune chronic idiopathic neutropenia of adults (NI-CINA). His work utilizes Gfi1 as a molecular probe to understand both normal myeloid development and innate immune action, as well as marrow failure and transformation.
PhD: Immunology and Molecular Pathology, University of Florida, Gainesville, FL.
Postdoctoral Fellow: Fox Chase Cancer Center.
Nayak RC, Trump LR, Aronow BJ, Myers K, Mehta P, Kalfa T, Wellendorf AM, Valencia CA, Paddison PJ, Horwitz MS, Grimes HL#, Lutzko C#, Cancelas JA#. Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells. J Clin Invest. 2015 Aug 3;125(8):3103-16. # shared corresponding author.
Velu CS, Chaubey A, Phelan JD, Horman SR, Wunderlich M, Guzman ML, Jegga AG, Zeleznik-Le NJ, Chen J, Mulloy JC, Cancelas JA, Jordan CT, Aronow BJ, Marcucci G, Bhat B, Gebelein B, Grimes HL. Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity. J Clin Invest. 2014 Jan;124(1):222-36.
Phelan JD, Saba AI, Olsson A, Zeng H, Kosan C, Messer MS, Hildeman D, Aronow B, Möröy T, Grimes HL. Growth factor independent-1 maintains Notch1-dependent transcriptional programming of lymphoid precursors. PLoS Genetics. 2013;9(9):e1003713.
Khandanpour C*, Phelan JD*, Vassen L, Schutte J, Chen R, Horman SR, Gaudreau MC, Krongold J, Zhu J, Paul WE, Duhrsen U, Gottgens B, Grimes HL# Moroy T#. Growth factor independence 1 (Gfi1) antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia. Cancer Cell. 2013 Feb 11;23(2):200-14. * equal first author, # shared corresponding author.
Horman SR, Velu CS, Chaubey A, Bourdeau T, Zhu J, Paul WE, Gebelein B, Grimes HL. Gfi1 integrates progenitor versus granulocytic transcriptional programming. Blood. 2009 May 28;113(22):5466-75.
Velu CS, Baktula AM, Grimes HL. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood. 2009 May 7;113(19):4720-8.
Horman SR, Velu CS, Chaubey A, Bourdeau T, Zhu J, Paul WE, Gebelein B, Grimes HL. Gfi1 integrates progenitor versus granulocytic transcriptional programming. Blood. 2009 May 28;113(22):5466-75.
Li-Kroeger D, Witt LM, Grimes HL, Cook TA, Gebelein B. Hox and senseless antagonism functions as a molecular switch to regulate EGF secretion in the Drosophila PNS. Dev Cell. 2008 Aug;15(2):298-308.
Zarebski1 A, Velu CS, Baktula AM, Bourdeau T, Horman SR, Basu S, Bertolone SJ, Horwitz M, Hildeman DA, Trent JO, Grimes HL. The Human Severe Congenital Neutropenia-Associated Gfi1N382S Mutant Blocks Murine Granulopoiesis Through CSF1. Immunity. 2008 Mar;28(3):370-80.
Person RE, Li FQ, Duan Z, Benson KF, Wechsler J, Papadaki HA, Eliopoulos G, Kaufman C, Bertolone SJ, Nakamoto B, Papayannopoulou T, Grimes HL, Horwitz M. Gfi1 Proto-Oncogene Mutation Causes Human Neutropenia and Targets Neutrophil Elastase. Nature Genetics. 2003 March 1;30: 295 - 300.
Fukun Guo, PhD
studies Rho GTPases and T and B lymphocyte development and function.
Rho GTPases and T and B lymphocyte development and function
BS: Jilin University, Changchun, Jilin, China, 1994.
MS: Academy of Military Medical Sciences, Beijing, China, 1997.
PhD: Southern Medical University, Guangzhou, Guangdong, China, 2000.
Postdoctoral Research Associate: University of Tennessee, Memphis, TN, 2000-2002; Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 2002-2004.
Research Associate: Southern Medical University, Guangzhou, Guangdong, China, 2000; Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 2004.
Research Instructor: Cincinnati Children’s Hospital Medical Center, Cincinnati, OH. 2005-2009.
Yang JQ, Kalim KW, Li Y, Zhang S, Hinge A, Filippi MD, Zheng Y, Guo F3. RhoA orchestrates glycolysis for Th2 cell differentiation and allergic airway inflammation. J Allergy Clin Immunol. 2016;137(1):231.e4.
Zhang S, Konstantinidis DG, Yang JQ, Mizukawa B, Kalim K, Lang RA, Kalfa TA, Zheng Y, Guo F. Gene targeting RhoA reveals its essential role in coordinating mitochondrial function and thymocyte development. Journal of Immunology. 2014;193(12):5973.
Guo F, Li J, Zhang S, Du W, Amarachintha S, Sipple J, Phelan J, Grimes HL, Zheng Y, Pang Q. mTOR kinase inhibitor sensitizes T-cell lymphoblastic leukemia for chemotherapy-induced DNA damage via suppressing FANCD2 expression. Leukemia. 2014;28(1):203.
Guo F, Li J, Du W, Zhang S, O'Connor M, Thomas G, Kozma S, Zingarelli B, Pang Q, Zheng Y. mTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells. Leukemia. 2013;27(10):2040.
Guo F, Zhang S, Grogg M, Cancelas JA, Varney ME, Starczynowski DT, Du W, Yang JQ, Liu W, Thomas G, Kozma S, Pang Q, Zheng Y. Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis. Haematologica. 2013;98(9):1353.
Zhang S, Zhou X, Lang RA, Guo F. RhoA of the Rho family small GTPases is essential for B lymphocyte development. PLoS One. 2012.7(3):e33773.
Guo F, Zhang S, Tripathi P, Mattner J, Phelan J, Sproles A, Mo J, Wills-Karp M, Grimes HL, Hildeman D, Zheng Y. Distinct roles of Cdc42 in thymopoiesis and effector and memory T cell differentiation. PLoS One. 2011;6(3):e18002.
Guo F, Hildeman D, Tripathi P, Velu CS, Grimes HL, Zheng Y. Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(43):18505.
Guo F, Velu CS, Grimes HL, Zheng Y. Rho GTPase Cdc42 is essential for B lymphocyte development and activation. Blood. 2009;114(14):2909.
Guo F, Cancelas JA, Hildeman D, Williams DA, Zheng Y. Rac GTPase isoforms, Rac1 and Rac2, play a redundant and crucial role in T-cell development. Blood. 2008;112(5):1767.
Novel Signaling Function of Cdc42 GTPase in vivo. Principal Investigator. National Institutes of Health. 2014-2018. R01 GM108661.
Novel therapeutics of targeting mTOR pathway in T-cell leukemia. Principal Investigator. National Institutes of Health. 2015-2017. R21 CA198358-01.
Pilot Award. Principal Investigator. National Institutes of Health. 2016. P30DK090971.
Gang Huang, PhD Member, Division of Experimental Hematology & Cancer Biology
focuses on genetic and epigenetic regulations of normal blood cell development and leukemia. His team demonstrated that AML1/CBFβ and mixed-lineage leukemia (MLL) protein form a regulatory complex, which is important for normal blood development and acts as a tumor suppressor in leukemia.
Research in Dr. Huang’s laboratory focuses on genetic and epigenetic regulations of blood cell normal development and leukemia. The lab first demonstrated that AML1/CBFβ (a hetero-dimer transcription factor) and mixed-lineage leukemia (MLL) protein (an enzyme which methylates lysine 4 of histone H3 tails), form a regulatory complex, which is important for normal blood development and acts as a tumor suppressor in leukemia. Mutations in either one of these three genes account for majority of acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndromes (MDS).
The lab also found that the AML1/CBFβ/MLL complex regulates another transcription factor, PU.1, through the upstream regulatory region of the PU.1 gene and that the epigenetic changes of the histone tails occurring in the PU.1 regulatory region correlate with the PU.1 expression level. PU.1 expression level changes are critical for blood cell differentiation and dysregulation of PU.1 dosages leading to leukemia.
This research will provide new insight into the interplay between genetics and epigenetics in normal blood development and leukemia. It will also help to develop generic drugs for most of the AML, ALL and MDS, which will benefit the future clinical treatments.
Staber PB, Zhang P, Ye M, Welner R, Nombela-Arrieta C, Bach C, Kerenyi M, Bartholdy BA, Zhang H, Alberich-Jorda M, Lee S, Yang H, Ng F, Zhang J, Leddin M, Silberstein LE, Hoefler G, Orkin S, Gottgens B, Rosenbauer F, Huang G, Tenen DG. Sustained PU.1 Levels Balance Cell Cycle Regulators to Prevent Exhaustion of Adult Hematopoietic Stem Cells. Mol Cell. 2013.
Hirai H, Kamio N, Huang G, Matsusue A, Ogino S, Kimura N, Satake S, Ashihara E, Imanishi J, Tenen MD, DG, Maekawa T. Cyclic AMP Responsive Element Binding proteins are involved in “emergency” granulopoiesis through the upregulation of CCAAT/Enhancer Binder Protein. PlosONE. 2013
Zhang Y, Chen A, Yan XM, Huang G. Disordered epigenetic regulation in MLL-related leukemia. Int J Hematol. 2012 Oct;96(4):428-37.
Zhang Y, Yan XM, Sashida G, Zhao XH, Rao YL, Goyama S, Whitman SP, Zorko N, Bernot K, Conway R, Witte D, Wang QF, Tenen DG, Xiao ZJ, Marcucci G, Mulloy J, Grimes HL, Caligiuri MA, Huang G. Mll partial tandem duplication (Mll-PTD) causes abnormal hematopoiesis in mice by reprogramming, enhancing self-renewal, lineage skewing and blocking myeloid differentiation. Blood. 2012 Aug 2;120(5):1118-29.
Zorko N, Bernot KS, Whitman SP, Siebenaler RF, Ahmed E, Marcucci GG, Yanes DA, McConnell KK, Mao C. Kalu C, Zhang XL, Jarjoura D, Dorrance AM, Lee BH, Huang G, Marcucci G, Caligiuri MA. Mll Partial Tandem Duplication and Flt3-Internal Tandem Duplication in a Double Knock-in Mouse Recapitulates Features of Counterpart Human Acute Myeloid Leukemias. Blood. 2012 Aug 2;120(5):1130-6.
Huang G, Zhao XH, Wang L, Elf S, Xu H, Zhao XY, Sashida G, Zhang Y, Liu Y, Lee J, Menendez S, Yang YY, Yan XM, Zhang P, Tenen DG, Osato M, Hsieh JDJ, Nimer SD. The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations. Blood. 2011;118(25):6544-52.
Wang L, Gural A, Sun XJ, Zhao X, Perna F, Huang G, Hatlen MA, Vu L, Liu F, Xu H, Asai T, Xu H, Deblasio T, Menendez S, Voza F, Jiang Y, Cole PA, Zhang J, Melnick A, Roeder RG, Nimer SD. The leukemogenicity of AML1-ETO is dependent on site-specific lysine Acetylation. Science. 2011;333(6043):765-9.
Huang G, Zhang P, Hirai H, Elf S, Yan XM, Chen Z, Koschmieder S, Okuno Y, Dayaram T, Growney JD, Shivdasani RA, Gilliland DG, Speck NA, Nimer SD, Tenen DG. PU.1 is a major downstream target of AML1/RUNX1 in adult hematopoiesis. Nat Genet. 2008;40:51-60.
Theodosia A. Kalfa, MD, PhD
Signaling in erythrocytes; erythropoiesis; sickle cell disease; reactive oxygen species
Visit the Kalfa Lab.
MD: Aristotle University Medical School, Thessaloniki, Greece, 1990.
PhD: Aristotle University Medical School, Thessaloniki, Greece, 1997.
Residency: University Of North Carolina, Chapel Hill, NC, 1999.
Fellowship: Duke University Medical Center, Durham, NC, 2003.
Certification: Hematology / oncology, American Board of Pediatrics, 2004; Pediatrics, American Board of Pediatrics, 2000; ECFMG Certification, 1995.
Licenses: Full and unrestricted medical license (OH Medical Board), 2003-present; full and unrestricted license of medical practice in Greece, 1990-present.
George A, Pushkaran S, Konstantinidis DG, Koochaki S, Malik P, Mohandas N, Zheng Y, Joiner CH, Kalfa TA. Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood. 2013 Mar 14;121(11):2099-107.
Konstantinidis DG, Pushkaran S, Johnson JF, Cancelas JA, Manganaris S, Harris CE, Williams DA, Zheng Y, Kalfa TA. Signaling and cytoskeletal requirements in erythroblast enucleation. Blood. 2012 Jun 21;119(25):6118-27.
Hammill AM, Risinger MA, Joiner CH, Keddache M, Kalfa TA. Compound heterozygosity for two novel mutations in the erythrocyte protein 4.2 gene causing spherocytosis in a Caucasian patient. Br J Haematol. 2011 Jan 31.
Kalfa TA. Anchoring at an island to relieve stress. Blood. 2011 Jan 20;117(3):748-9.
Mizukawa B, George A, Pushkaran S, Weckbach L, Kalinyak K, Heubi JE, Kalfa TA. Cooperating G6PD mutations associated with severe neonatal hyperbilirubinemia and cholestasis. Pediatr Blood Cancer. 2010 Oct 14.
Konstantinidis DG, George A, Kalfa TA. Rac GTPases in erythroid biology. Transfus Clin Biol. 2010 Sep;17(3):126-30.
Mulloy JC, Cancelas JA, Filippi MD, Kalfa TA, Guo F, Zheng Y. Rho GTPases in hematopoiesis and hemopathies. Blood. 2010 Feb 4;115(5):936-47.
Wang D, Zhang W, Kalfa TA, Grabowski G, Davies S, Malik P, Pan D. Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19958-63.
Rho GTPases in Terminal Erythroid Maturation. Principal Investigator. NIH/NHLBI. Sep 2012-Jun 2016. #1R01HL116352.
Cincinnati Center of Excellence in Hemoglobinopathies Research. Co-investigator. NIH/NHLBI. Aug 2013–May 2018. # U01 HL117709.
Kakajan Komurov, PhD Member, Cancer Biology and Neural Tumors Program
Computational and experimental approaches to characterize targetable cancer vulnerabilities; oncogene-induced stress pathways in cancer therapy; the study of mechanisms, implications and therapeutic vulnerabilities imposed by the severe epigenetic defects in a subset of cancers
Visit the Komurov Lab.
Dr. Komurov focuses on computational and systems biology of cancer. His research interests are centered on integrating in silico, in vitro and in vivo analyses to model and target cancer cell vulnerabilities. Research in the Komurov lab also involves development of new computational tools, including methodology and software, for effective integration of large ‘omics and prior functional interaction datasets for knowledge-based data analyses.
Adams AK, Bolanos LC, Dexheimer PJ, Karns RA, Aronow BJ, Komurov K, Jegga AG, Casper KA, Patil YJ, Wilson KM, Starczynowski DT, Wells SI. IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival. Oncotarget. 2015 Oct 26.
Segura-Cabrera A, Singh N, Komurov K. An integrated network platform for contextual prioritization of drugs and pathways. Mol Biosyst. 2015 Oct 13;11(11):2850-9.
Singh N, Joshi R, Komurov K. HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive. Sci Signal. 2015 May 26;8(378):ra52.
Gopal YN, Rizos H, Chen G, Deng W, Frederick DT, Cooper ZA, Scolyer RA, Pupo G, Komurov K, Sehgal V, Zhang J, Patel L, Pereira CG, Broom BM, Mills GB, Ram P, Smith PD, Wargo JA, Long GV, Davies MA. Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. Cancer Res. 2014 Dec 1;74(23):7037-47.
Fang J, Barker B, Bolanos L, Liu X, Jerez A, Makishima H, Christie S, Chen X, Rao DS, Grimes HL, Komurov K, Weirauch MT, Cancelas JA, Maciejewski JP, Starczynowski DT. Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-κB gene network. Cell Rep. 2014 Sep 11;8(5):1328-38.
Kim HS, Mendiratta S, Kim J, Pecot CV, Larsen JE, Zubovych I, Seo BY, Kim J, Eskiocak B, Chung H, McMillan E, Wu S, De Brabander J, Komurov K, Toombs JE, Wei S, Peyton M, Williams N, Gazdar AF, Posner BA, Brekken RA, Sood AK, Deberardinis RJ, Roth MG, Minna JD, White MA. Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell. 2013 Oct 24;155(3):552-66.
Matsuo K, Nishimura M, Komurov K, Shahzad MM, Ali-Fehmi R, Roh JW, Lu C, Cody DD, Ram PT, Loizos N, Coleman RL, Sood AK. Platelet-derived growth factor receptor alpha (PDGFRα) targeting and relevant biomarkers in ovarian carcinoma. Gynecol Oncol. 2014 Jan;132(1):166-75.
Lane A, Segura-Cabrera A, Komurov K. A comparative survey of functional footprints of EGFR pathway mutations in human cancers. Oncogene. 2014 Oct 23;33(43):5078-89.
Ward SE, Kim HS, Komurov K, Mendiratta S, Tsai PL, Schmolke M, Satterly N, Manicassamy B, Forst CV, Roth MG, García-Sastre A, Blazewska KM, McKenna CE, Fontoura BM, White MA. Host modulators of H1N1 cytopathogenicity. PLoS One. 2012;7(8):e39284.
Komurov K, Tseng JT, Muller M, Seviour EG, Moss TJ, Yang L, Nagrath D, Ram PT. The glucose-deprivation network counteracts lapatinib-induced toxicity in resistant ErbB2-positive breast cancer cells. Mol Syst Biol. 2012;8:596.
Modeling and targeting the hexosamine pathway in drug resistance. Principal Investigator. Susan G. Komen for the Cure. Aug 2013-Jul 2016. CCR13263034.
Exploiting proteotoxic stress in therapy-refractory HER2+ breast cancers. Principal Investigator. National Cancer Institute. Apr 2015-Mar 2020. 1R01CA193549-01.
Global Transcript Shortening in cancers. Principal Investigator. Cincinnati Children's Hospital Medical Center RIP award. Sep 2015-Aug 2016.
Ashish R. Kumar, MD, PhD Director, Langerhans Cell Histiocytosis Center
Director, Langerhans Cell Histiocytosis Center
Director, Pediatric Hematology/Oncology Fellowship Program
Member, Division of Bone Marrow Transplantation & Immune Deficiency
Childhood cancer and blood disorders; immune deficiency
Dr. Kumar received his medical degree from L.T.M. Medical College, Mumbai, India, his PhD in anatomy and cell biology from the University of Iowa, pediatric residency training at the Mayo Clinic and fellowship in pediatric hematology / oncology / BMT at the University of Minnesota. He was appointed to the faculty of the University of Minnesota in the Department of Pediatrics where he was a member of the programs in pediatric leukemia and global pediatrics. He is currently an associate professor of pediatrics in the Division of Bone Marrow Transplantation and Immune Deficiency at Cincinnati Children's within the University of Cincinnati College of Medicine. Dr. Kumar’s laboratory is engaged in researching the biology of infant leukemia. Discoveries made in his laboratory have significantly enhanced the current understanding of leukemia. Dr. Kumar is also active in education. He has delivered invited lectures and grand round presentations on various topics.
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MD: LTM Medical College, Mumbai, India.
Residency: Mayo Clinic, Rochester, MN.
Fellowship: University of Minnesota, Minneapolis, MN.
PhD: University of Iowa, Iowa City, IA.
Certification: General Pediatrics; Pediatric Hematology/Oncology Subspecialty.
Licenses: State of Ohio; State of Minnesota.
Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, Kostyuchenko L, Genel F, Kütükcüler N, Karaca N, Gonzalez-Granado L, Abbott J, Al-Zahrani D, Rezaei N, Baz Z, Thiel J, Ehl S, Marodi L, Orange JS, Sawalle-Belohradsky J, Keles S, Holland SM, Sanal Ö, Ayvaz DC, Tezcan I, Al-Mousa H, Alsum Z, Hawwari A, Metin A, Matthes-Martin S, Hönig M, Schulz A, Picard C, Barlogis V, Gennery A, Ifversen M, van Montfrans J, Kuijpers T, Bredius R, Dückers G, Al-Herz W, Pai SY, Geha R, Notheis G, Schwarze CP, Tavil B, Azik F, Bienemann K, Grimbacher B, Heinz V, Gaspar HB, Aydin R, Hagl B, Gathmann B, Belohradsky BH, Ochs HD, Chatila T, Renner ED, Su H, Freeman AF, Engelhardt K, Albert MH; inborn errors working party of EBMT. DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients. J Clin Immunol. 2015 Feb;35(2):189-98.
Roychoudhury J, Clark JP, Gracia-Maldonado G, Unnisa Z, Wunderlich M, Link KA, Dasgupta N, Aronow B, Huang G, Mulloy JC, Kumar AR. MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia. Blood. 2015;125(16):2544-52.
Marsh RA, Rao MB, Gefen A, Bellman D, Mehta PA, Khandelwal P, Chandra S, Jodele S, Myers KC, Grimley M, Dandoy C, El-Bietar J, Kumar AR, Leemhuis T, Zhang K, Bleesing JJ, Jordan MB, Filipovich AH, Davies SM. Experience with Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Hematopoietic Cell Transplantation in Patients with Nonmalignant Diseases Reveals Good Outcomes and That the Risk of Mixed Chimerism Depends on Underlying Disease, Stem Cell Source, and Alemtuzumab Regimen. Biol Blood Marrow Transplant. 2015 Aug;21(8):1460-70.
Cai X, Gao L, Teng L, Ge J, Oo ZM, Kumar AR, Gilliland DG, Mason PJ, Tan K, Speck NA. Runx1 Deficiency Decreases Ribosome Biogenesis and Confers Stress Resistance to Hematopoietic Stem and Progenitor Cells. Cell Stem Cell. 2015 Jul;pii:S1934-5909(15)00262-3.
Karkare S, Chhipa RR, Anderson J, Liu X, Henry H, Gasilina A, Nassar N, Roychoudhury J, Clark JP, Kumar A, Pauletti GM, Ghosh PK, Dasgupta B. Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell-cycle arrest and suppresses glioblastoma growth. Clin Cancer Res. 2014 Jan;20(1):199-212.
Khandelwal P, Lawrence J, Filipovich AH, Davies SM, Bleesing JJ, Jordan MB, Mehta P, Jodele S, Grimley MS, Kumar A, Myers K, Marsh RA. The successful use of alemtuzumab for treatment of steroid-refractory acute graft-versus-host disease in pediatric patients. Pediatr Transplant. 2014 Feb;18(1):94.
Liu X, Chhipa RR, Pooya S, Wortman M, Yachyshin S, Chow LM, Kumar A, Zhou X, Sun Y, Quinn B, McPherson C, Warnick RE, Kendler A, Giri S, Poels J, Norga K, Viollet B, Grabowski GA, Dasgupta B. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sci USA. 2014 Jan;111(4):E435-44.
Zhou J, Wu J, Li B, Liu D, Yu J, Yan X, Zheng S, Wang J, Zhang L, Zhang L, He F, Li Q, Chen A, Zhang Y, Zhao X, Guan Y, Zhao X, Yan J, Ni J, Nobrega MA, Löwenberg B, Delwel R, Valk PJ, Kumar A, Xie L, Tenen DG, Huang G, Wang QF. PU.1 is Essential for MLL Leukemia Partially via Crosstalk with the MEIS/HOX Pathway. Leukemia. 2014 Jul;28(7):1436-48.
Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, Atkinson TP, Uzel G, Matthews HF, Mustillo PJ, Lewis DB, Kavadas FD, Hanson IC, Kumar AR, Geha RS, Douek DC, Holland SM, Freeman AF, Su HC. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. The Journal of allergy and clinical immunology. 2014 Jun;133(6):1667-75.
Marsh RA, Rao K, Satwani P, Lehmberg K, Müller I, Li D, Kim MO, Fischer A, Latour S, Sedlacek P, Barlogis V, Hamamoto K, Kanegane H, Milanovich S, Margolis DA, Dimmock D, Casper JT, Douglas DN, Amrolia PJ, Veys P, Kumar AR, Jordan BM, Bleesing J, Filipovich A. Allogeneic Hematopoietic Cell Transplantation for XIAP Deficiency: An International Survey Reveals Poor Outcomes. Blood. 2013 Feb 7;121(6):877-83.
Role of MEIS1 in hematopoiesis and hematopoietic transformation. Principal Investigator. National Institutes of Health/National Heart, Lung, and Blood Institute. Jul 2012-Jun 2017.
Novel therapeutics of targeting mTOR pathway in T-cell leukemia. Co-investigator. National Institutes of Health/National Cancer Institute. Jul 2015-Jun 2017.
Adam Lane, PhD
has methodological research interests in designs for phase I/II clinical trials, survival analysis and structural equation modeling. Dr. Lane is also a dedicated collaborator with both clinical and basic science researchers in bone marrow transplantation, hematology, oncology and cancer biology.
Clinical trials; survival analysis; structural equation modeling
Dr. Lane joined Cincinnati Children's in July 2013. He has published novel statistical methods in the areas of adaptive and optimal experimental designs with applications to phase I and phase II clinical trials. As a graduate student he received funding from the NIH to spend the fall semester of 2011 at the University of Cambridge in the Isaac Newton Institute for Mathematical Sciences. He has also received NSF travel awards to present his research at national and international conferences.
Lane A, Ping Y, Flournoy N. Information in a two-stage adaptive optimal design. J Statist Plan Inference. 2014 Jan 144:173-87.
Lane A, Flournoy N. Two-stage adaptive optimal design with fixed first stage sample size. Journal of Probability and Statistics. 2012.
Qing Richard Lu, PhD Scientific Director, Brain Tumor Center
and his lab study the transcriptional and signaling regulatory networks that control gliogenesis (oligodendrocyte, astrocyte and Schwann cell), brain cancer stem/initiating cell growth and myelinogenesis. Dr. Lu lab utilizes transgenic and gene targeting mouse models to understand the molecular mechanisms underlying demyelinating diseases and brain tumorigenesis and to develop new therapies for neurodegenerative diseases and brain cancers.
Visit the Lu Lab.
Scientific Director, Brain Tumor Center
BS: Peking Normal University, Beijing, China, 1988.
MS: Rutgers University, Piscataway, NJ, 1993.
PhD: Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, 1997.
Postdoctoral Fellow: Dana Farber Cancer Institute, Harvard Medical School, Cambridge, MA, 1997-2002.
Lu F, Chen Y, Zhao C, Wang H, He D, Xu L, Wang J, He X, Deng Y, Lu EE, Liu X, Verma R, Bu H, Drissi R, Fouladi M, Stemmer-Rachamimov AO, Burns D, Xin M, Rubin JB, Bahassi EM, Canoll P, Holland EC, Lu QR. Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma. Cancer Cell. 2016.
He D, Marie C, Zhao C, Kim B, Wang J, Deng Y, Clavairoly A, Frah M, Wang H, He X, Hmidan H, Jones BV, Witte D, Zalc B, Zhou X, Choo DI, Martin DM, Parras C, Lu QR. Chd7 Cooperates with Sox10 and Regulates the Onset of CNS Myelination and Remyelination. Nature Neuroscience. 2016. doi:10.1038/nn.4258.
Zhao C, Deng Y, Liu L, Yu K, Zhang L, Wang H, He H, Wang J, Lu C, Wu LN, Weng Q, Mao M, Li J, van Es JH, Xin M, Parry L, Goldman SA, Clevers H, Lu QR. Dual Regulatory Switch Through Interactions of Tcf7l2/Tcf4 with Stage-Specific Partners Propels Oligodendroglial Maturation. Nature Communications. 2016;7:10883 doi: 10.1038/ncomms10883.
Zhang L*, He X*, Liu L, Jiang M, Zhao C, Wang H, He D, Zheng T, Zhou X, Hassan A, Ma Z, Xin M, Sun Z, Lazar MA, Goldman SA, Olson EN, Lu QR. Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch. Developmental Cell. 2016 Feb 8;36(3):316-30.
Shen YA*, Chen Y*, Dao DQ, Mayoral SR, Wu L, Meijer D, Ullian EM, Chan JR#, Lu QR#. Phosphorylation of LKB1/Par-4 Establishes Schwann Cell Polarity to Initiate and Control Myelin Extent. Nature Communications. 2014 Sep 26;5:4991. # Co-corresponding author.
He X, Zhang L, Chen Y, Remke M, Shih D, Lu F, Wang H, Deng Y, Yu Y, Xia Y, Wu X, Ramaswamy V, Hu T, Wang F, Zhou W, Burns DK, Kim SH, Kool M, Pfister S, Weinstein LS, Pomeroy S, Gilbertson R, Rubin JB, Hou Y, Wechsler-Reya R, Taylor MD, Lu QR. The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog driven Medulloblastoma. Nature Medicine. 2014 Sep;20(9):1035-42.
Yu Y, Chen Y, Kim B, Wang H, Zhao C, He X, Liu L, Liu W, Wu, LM, Mao M, Chan JR, Wu J, Lu QR. Olig2 targets chromatin remodelers to enhancers to initiate oligodendrocyte differentiation. Cell. 2013 Jan 17;152(1-2):248–261.
Weng Q, Chen Y, Wang H, Xu X, Yang B, He Q, Shou W, Higashi Y, van den Berghe V, Seuntjens E, Kernie SG, Bukshpun P, Sherr EH, Huylebroeck D, Lu QR. Dual-mode modulation of Smad signaling by Smad-interacting protein Sip1 is required for myelination in the central nervous system. Neuron. 2012 Feb 23;73(4):713-28.
Chen Y, Wang H, Yoon SO, Xu X, Hottiger MO, Svaren J, Nave KA, Kim HA, Olson EN, Lu QR. HDAC-mediated Deacetylation of NF-κB is Critical for Schwann cell Myelination. Nat Neurosci. 2011 April;14(4):437-41.
Zhao XH, He X, Han X, Yu Y, Ye F, Chen Y, Hoang T, Xu X, Mi QS, Xin M, Wang F, Appel B, Lu QR. MicroRNA-Mediated Control of Oligodendrocyte Differentiation. Neuron. 2010 Mar 11;65(5):612-26.
A Novel Model of Medulloblastoma to Define Cancer Pathways and Molecular Targets. Principal Investigator. National Institutes of Health (NINDS). Apr 2012–Mar 2017. 1R01NS078092.
Molecular Mechanisms of Oligodendrocyte Differentiation and Myelination. Principal Investigator. National Institutes of Health (NINDS). Sep 2015-Aug 2020. 1R01NS072427.
Chromatin Remodeling Control of CNS Myelination and Remyelination. Principal Investigator. National Institutes of Health (NINDS). Apr 2012–Mar 2017. 1R01NS075243-01.
Carolyn M. Lutzko, PhD
studies the regulation of human pluripotent stem cells, somatic cell reprogramming in iPSC, human embryonic stem cell physiology and differentiation, hESC, and cystic fibrosis.
Field Service Associate Professor, UC Department of Pediatrics
Regulating human pluripotent stem cell; somatic cell reprogramming in iPSC; human embryonic stem cell physiology and differentiation; hESC; cystic fibrosis
BA: University of Guelph, S.Sc. Hon, Molecular Biology and Genetics Guelph, Ontario, Canada 1992.
PhD: University of Toronto, PhD Department of Laboratory Medicine Toronto, Ontario, Canada 1999.
Fellowship: Childrens Hospital Los Angeles Department of Pediatrics Division of Research Immunology/BMT Los Angeles, CA, 1999-2002.
Mishra S, Wang X, Smiley N, Bui KC, Senadheera D, Chang D, Lutzko C. In utero delivery of lentiviral supernatant to the amniotic fluid genetically modifies airway epithelial progenitors. American Journal of Respiratory Cellular and Molecular Biology. 2010.
Bui KC, Senadheera D, Wang X, Hendrickson B, Friedlich P, Lutzko C. Isolation of progenitors from the peripheral blood of patients with acute respiratory or cardiac failure who required ECMO support. American Journal of Respiratory and Critical Care Medicine. 2010 181:226-237.
Harb R, Xie G, Lutzko C, Guo Y, Wang X, Hill CK, Kanel GC, DeLeve LD. Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury. Gastroenterology. 2009 137:704-12.
Chang D, Tsai S, Wang X, Xia P, Senadheera D, Lutzko C. Molecular characterization of the human nanog protein. Stem Cells. 2009 27:812-821.
Jiang X, Gwye Y, Lutzko C, Lawlor ER. Isolation and characterization of neural crest stem cells derived from in vitro – differentiated human embryonic stem cells. Stem Cells and Development. 2009 18:259-270.
Melchior K, Weib J, Zaehres H, Yong-Mi K, Lutzko C, Roosta N, Hescheler J, Muschen M. The WNT receptor FZD7 contributes to self-renewal of signaling of human embryonic stem cells. Journal of Biological Chemistry. 2008 389:897-903.
Liebler J, Lutzko C, Banfalvi A, Senadheera D, Crandall ED, Borok Z. Retention of human bone marrow-derived cells in murine lungs following bleomycin injury. American Journal of Pathology-Lung and Cellular Molecular Physiology. 2008 295:285-292.
Rodriguez RT, Velkey JM, Lutzko C, Seerke R, Kohn DB, O’Shea KS, Firpo MT. Manipulation of OCT4 levels in human embryonic stem cells results in induction of differential cell types. Journal of Experimental Biology & Medicine. 2007 232:1368-80.
Hendrickson B, Senadheera D, Mishra S, Bui KC, Wang XC, Chan B, Petersen, D, Pepper K, Lutzko C. Development of lentiviral vectors with regulated respiratory epithelia expression in vivo. American Journal of Respiratory Cellular and Molecular Biology. 2007 37:414-23.
Punam Malik, MD Marjory J. Johnson Chair of Gene and Cell Therapy
works to correct the gene responsible for sickle cell anemia. One of the lab’s major projects uses gene therapy to treat sickle cell disease. The lab is also interested in gene therapy for other diseases. She has developed various methods for delivering corrective genes to cells, improving methods for gene therapy in general.
Marjory J. Johnson Chair of Gene and Cell Therapy
Director, Cincinnati Comprehensive Sickle Cell Program
Program Leader, Hematology and Gene Therapy Program
MBBS: University of Delhi, New Delhi, India, 1985.
MD: University of Delhi, New Delhi, India, 1989.
MS: University of Maryland, Baltimore, MD, 1991.
Fellowship: Children's Hospital Los Angeles, University of Southern California, 1995.
Arumugam P, Malik P. Genetic therapy for beta-thalassemia: from the bench to the bedside. Hematology Am Soc Hematol Educ Program. 2010;2010:445-50.
Perumbeti A, Malik P. Therapy for beta-globinopathies: a brief review and determinants for successful and safe correction. Ann N Y Acad Sci. 2010 Aug;1202:36-44. Review.
Perumbeti A, Malik P. Genetic correction of sickle cell anemia and beta-thalassemia: progress and new perspective. Scientific World Journal. 2010 Apr 13;10:644-54. Review.
Sundaram N, Tailor A, Mendelsohn L, Wansapura J, Wang X, Higashimoto T, Pauciulo MW, Gottliebson W, Kalra VK, Nichols WC, Kato GJ, Malik P. High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension. Blood. 2010 Jul 8;116(1):109-12.
Arumugam PI, Urbinati F, Velu CS, Higashimoto T, Grimes HL, Malik P. The 3' region of the chicken hypersensitive site-4 insulator has properties similar to its core and is required for full insulator activity. PLoS One. 2009 Sep 10;4(9):e6995.
Arumugam PI, Higashimoto T, Urbinati F, Modlich U, Nestheide S, Xia P, Fox C, Corsinotti A, Baum C, Malik P. Genotoxic potential of lineage-specific lentivirus vectors carrying the beta-globin locus control region. Mol Ther. 2009 Nov;17(11):1929-37.
Perumbeti A, Higashimoto T, Urbinati F, Franco R, Meiselman HJ, Witte D, Malik P. A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. Blood. 2009 Aug 6;114(6):1174-85.
Urbinati F, Arumugam P, Higashimoto T, Perumbeti A, Mitts K, Xia P, Malik P. Mechanism of reduction in titers from lentivirus vectors carrying large inserts in the 3'LTR. Mol Ther. 2009 Sep;17(9):1527-36.
Ruhikanta A. Meetei, PhD Member, Experimental Hematology and Cancer Biology
focuses on functional analysis of Fanconi anemia gene products. The major research focus includes identification of new FA genes and signal transduction pathways that regulate DNA-damage-induced activation of the FA-core complex.
Member, Experimental Hematology and Cancer Biology
Fanconi anemia; chromosome instability; DNA repair; multiprotein complex
BS: Manipur University, India, 1989.
MS: Manipur University, India, 1992.
PhD: Indian Institute of Science, Bangalore, India, 2000.
Singh TR, Saro D, Ali AM, Zheng XF, Du CH, Killen MW, Sachpatzidis A, Wahengbam K, Pierce AJ, Xiong Y, Sung P, Meetei AR. MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM. Mol Cell. 2010 Mar 26;37(6):879-86.
Singh TR, Bakker ST, Agarwal S, Jansen M, Grassman E, Godthelp BC, Ali AM, Du CH, Rooimans MA, Fan Q, Wahengbam K, Steltenpool J, Andreassen PR, Williams DA, Joenje H, de Winter JP, Meetei AR. Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M. Blood. 2009 Jul 2;114(1):174-80.
Ali AM, Kirby M, Jansen M, Lach FP, Schulte J, Singh TR, Batish SD, Auerbach AD, Williams DA, Meetei AR. Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group. Hum Mutat. 2009 Jul;30(7):E761-70.
Ali AM, Singh TR, Meetei AR. FANCM-FAAP24 and FANCJ: FA proteins that metabolize DNA. Mutat Res. 2009 Jul 31;668(1-2):20-6. Review.
Singh TR, Ali AM, Busygina V, Raynard S, Fan Q, Du CH, Andreassen PR, Sung P, Meetei AR. BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase-double Holliday junction dissolvasome. Genes Dev. 2008 Oct 15;22(20):2856-68.
Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, Steltenpool J, Stone S, Dokal I, Mathew CG, Hoatlin M, Joenje H, de Winter JP, Wang W. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005 Sep;37(9):958-63.
Benjamin E. Mizukawa, MD Scholar, St. Baldrick's Foundation
is trained in pediatric hematology/oncology with a research emphasis in leukemia biology and novel therapeutics. His work is focused on understanding the role of small Rho GTPases in myeloid leukemia development and progression, with the translational goal of identifying new targets for drug development.
Scholar, St. Baldrick's Foundation
Pediatric leukemia and lymphoma; investigation of the role of small Rho GTPases in leukemogenesis and leukemic stem cell biology and their potential as therapeutic targets in acute myeloid leukemia; development of xenograft models for use in testing novel therapeutics.
MD: University of Utah, Salt Lake City, UT, 2004.
Residency: Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.
Fellowship: Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.
Certification: Pediatrics, 2008; Pediatric Hematology/Oncology, 2011.
Wunderlich M, Mizukawa B, Chou FS, Sexton C, Shrestha M, Saunthararajah Y, Mulloy JC. AML cells are differentially sensitive to chemotherapy treatment in a human xenograft model. Blood. 2013 Mar 21;121(12):e90-7.
Chou FS, Griesinger A, Wunderlich M, Lin S, Link KA, Shrestha M, Goyama S, Mizukawa B, Shen S, Marcucci G, Mulloy JC. The THPO/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO. Blood. 2012;120(4):709-19.
Mizukawa B, Wei J, Shrestha M, Wunderlich M, Chou FS, Griesinger A, Harris CE, Kumar AR, Zheng Y, Williams DA, Mulloy JC. Inhibition of Rac GTPase signaling and downstream pro-survival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia. Blood. 2011 118(19):5235-45.
Mizukawa B, George A, Pushkaran S, Weckbach L, Kalinyak K, Heubi JE, Kalfa TA. Cooperating G6PD mutations associated with severe neonatal hyperbilirubinemia and cholestasis. Pediatr Blood Cancer. 2011 56(5): 840-2.
Wunderlich M, Chou FS, Link KA, Mizukawa B, Perry RL, Carroll M, Mulloy JC. AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF, and IL-3. Leukemia. 2010; 24(10):1785-8.
James C. Mulloy, PhD Member, Experimental Hematology & Cancer Biology
Member, Experimental Hematology & Cancer Biology
BA: St. Anselm College, Manchester, NH, 1986.
MS: Rutgers University-University of Medicine and Dentistry, New Brunswick, NJ, 1989.
PhD: Rutgers University-University of Medicine and Dentistry, New Brunswick, NJ, 1992.
Goyama S, Schibler J, Gasilina A, Shrestha M, Lin S, Link KA, Chen J,
Whitman SP, Bloomfield CD, Nicolet D, Assi SA, Ptasinska A, Heidenreich
O, Bonifer C, Kitamura T, Nassar NN, Mulloy JC. UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO. Leukemia. 2016;30(3):728-39.
Maiques-Diaz A, Hernando M, Sánchez-López A, Rio-Machin A, Shrestha M, Mulloy JC, Cigudosa JC, Alvarez S. MAPK8-mediated stabilization of SP1 is essential for RUNX1-RUNX1T1 - driven leukaemia. Br J Haematol. 2016 Mar;172(5):807-10.
Benito JM, Godfrey L, Kojima K, Hogdal L, Wunderlich M, Geng H, Marzo I, Harutyunyan KG, Golfman L, North P, Kerry J, Ballabio E, Chonghaile TN, Gonzalo O, Qiu Y, Jeremias I, Debose L, O'Brien E, Ma H, Zhou P, Jacamo R, Park E, Coombes KR, Zhang N, Thomas DA, O'Brien S, Kantarjian HM, Leverson JD, Kornblau SM, Andreeff M, Müschen M, Zweidler-McKay PA, Mulloy JC, Letai A, Milne TA, Konopleva M. MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199. Cell Rep. 2015 Dec 29;13(12):2715-27.
Thowfeik FS, AbdulSalam SF, Wunderlich M, Wyder M, Greis KD, Kadekaro AL, Mulloy JC, Merino EJ. A ROS-Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds. Chembiochem. 2015 Nov;16(17):2513-21.
Glait-Santar C, Desmond R, Feng X, Bat T, Chen J, Heuston E, Mizukawa B, Mulloy JC, Bodine DM, Larochelle A, Dunbar CE. Functional Niche Competition Between Normal Hematopoietic Stem and Progenitor Cells and Myeloid Leukemia Cells. Stem Cells. 2015 Dec;33(12):3635-42.
Ågerstam H, Karlsson C, Hansen N, Sandén C, Askmyr M, von Palffy S, Högberg C, Rissler M, Wunderlich M, Juliusson G, Richter J, Sjöström K, Bhatia R, Mulloy JC, Järås M, Fioretos T. Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia. Proc Natl Acad Sci USA. 2015 Aug 25;112(34):10786-91.
Goyama S, Wunderlich M, Mulloy JC. Xenograft models for normal and malignant hematopoiesis. Blood. 2015 Apr;125(17):2630-2640.
Roychoudhury J, Clark JP, Gracia-Maldonado G, Unnisa Z, Wunderlich M, Link KA, Dasgupta N, Aronow B, Huang G, Mulloy JC, Kumar AR. MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia. Blood. 2015 Apr;125(16):2544-52.
Goyama S, Huang G, Kurokawa M, Mulloy JC. Posttranslational modifications of RUNX1 as potential anticancer targets. Oncogene. 2015 Jul;34(27):3483-92.
Vadukoot AK, AbdulSalam SF, Wunderlich M, Pullen ED, Landero-Figueroa J, Mulloy JC, Merino EJ. Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells. Bioorganic & Medicinal Chemistry. 2014 Dec;22(24):6885-92.
Conferring in vivo metabolic resistance to a highly selective anti-AML agent. Co-Investigator. National Institutes of Health/National Cancer Institute. May 2014-Apr 2017.
Rapid Suppression of Food Allergy with Anti-Fc Epsilon Rl Alpha Antibody. Co-Investigator. Food Allergy Research & Education Inc. Apr 2014-Mar 2017.
Suppression of IgE-Mediated Disease by Polyclonal Rapid Desensitization. Co-Investigator. National Institutes of Health/National Institute of Allergy and Infectious Diseases. Jul 2014-Jun 2019.
A new Hydrogen Peroxide-activated Agent that Selectively. Co-Principal Investigator. Center for Clinical and Translational Science and Training. Jul 2015-Jun 2016.
Nicolas Nassar, PhD
is a structural biologist interested in understanding the structure/function of signaling proteins, how they specifically bind and recognize regulators and targets, and in finding ways to inhibit their signaling in disease. His lab combines X-ray crystallography, site-directed mutagenesis, enzyme kinetics, and other biophysical techniques in its studies.
The major focus of our laboratory is to understand the regulation and signaling of the GTP-binding protein Ras and other Ras-like GTPases and to find small molecules that inhibit their activity in human cancers. Signaling by Ras-like GTPases is key to almost every cellular process and Ras is among the most mutated genes in human cancer. Despite this, a small molecule specifically targeting Ras activity has yet to enter clinical trials. Our research efforts encompass several methodologies, including protein crystallography, biophysical and biochemical studies, cellular functional assays, and ultimately, high throughput screenings of chemical libraries of small compounds that bind to and modulate GTPase signaling in cell line models.
We have identified several compounds that bind in vitro to Ras, inhibit cell proliferation of lung and other Ras-transformed cell lines, and decrease the activation of Erk-1/-2 and PI3K/AKT. Several ongoing questions stem from this finding: (i) we want to establish the mechanism of action(s) of these compounds. What gene or cellular process do they activate or silence downstream of Ras? Do they bind to Ras in cells and how specific is their binding? (ii) We are in the process of translating our findings to several disease models where Ras is hyperactivated, including both solid tumors such as lung adenocarcinomas, and MPNSTs and leukemias such as B-ALL.
We are also interested in the structure/function relationship of the multidomain protein tyrosine phosphatase (PTP) UBASH3B/Sts-1. Sts-1 was shown to be a target in triple negative breast cancer (TNBC). Our research is geared towards identifying small molecule inhibitors of the phosphatase activity of Sts-1. We have identified one such compound that inhibits the phosphatase activity of Sts-1 in vitro, decreases TNBC cell proliferation and decreases overall levels of phosphorylated proteins. We are currently testing structural analogs of our lead compound to further improve its potency.
PhD: University Joseph Fourier, Grenoble,France, 1992.
Postdoc: Max Plank Institut, Dortmund, Germany, 1996.
Research Associate: Cornell University, Ithaca, NY, 2000.
Assistant Professor: Stony Brook University, NY, 2006.
Research Assistant Professor: Stony Brook University, Stony Brook, NY, 2010.
Jackoncic J, Sondgeroth B, Carpino N, Nassar N. The 1.35 Å structure of the Phosphatase domain of the Suppressor of T Cell Receptor Signaling Protein in complex with Sulfate. Acta Cryst section F66, 2010 643-647.
Nassar N, Singh K, Garcia-Diaz M. Structure of the dominant negative S17N mutant of Ras. Biochemistry. 2010 49,1970-1974.
Ford B, Boykevisch S, Zhao C, Kunzelmann S, Bar-Sagi D, Herrmann C, Nassar N. Characterization of a Ras mutant with identical GDP- and GTP-bound structures. Biochemistry. 2009 48,11449-11457.
Carpino N, Chen Y, Nassar N, Hye-Won Oh. The Sts proteins target tyrosine phosphorylated, ubiquitinated proteins within TCR signaling pathways. in review. J. Immuno. 2009 46,3224-3231.
Chen Y, Jakoncic J, Parker KA, Carpino N, Nassar N. Structures of the Phosphorylated and VO3-bound 2H-Phosphatase Domain of Sts-2. Biochemistry. 2009 48, 8129-8135.
Chen Y, Jakoncic J, Carpino N, Nassar N. Structural and Functional Characterization of the 2H-phosphatase domain of Sts-2 reveals an Acid-Dependent Phosphatase Activity. Biochemistry. 2009 48,1681-1690.
Chen Y, Jakoncic J, Keller J, Wang J, Zheng X, Carpino N, Nassar N. Structural and functional characterization of the C-terminal domain of the ecdysteroid phosphate phosphatase from Bombyx mori. Biochemistry. 2008 47,12135-12145.
Mikhailik A, Ford B, Keller J, Chen Y, Nassar N, Carpino N. The C-terminal mutase-like domain of Sts-1 is important for its T-cell suppressor activity. Molecular Cell. 2007 27, 486-487.
Dao Pan, PhD
Hematopoietic stem cells; mesenchymal stem/progenitor cells; gene therapy; human genetics; translational research; lysosomal storage diseases
MS: Peking Normal University, Beijing, China, 1991.
PhD: University of Minnesota, Minneapolis, MN, 1997.
Wang X, Chiang A, Shin SC, Chen L, Pan D, Rawlings DJ, Miao CH. Intraosseous delivery of lentiviral vectors targeting factor VIII expression in platelets corrects murine Hemophilia A. Mol Ther. 2015 Feb 6;23(4):617-26.
El-Amouri SS, Dai D, Han JF, Brady RO, Pan D. Normalization and improvement of CNS deficits of mice with Hurler syndrome after long-term peripheral delivery of BBB-targeted Iduronidase. Mol Ther. 2014;22(12):2028-37.
Dai M, Han J, El-Amouri SS, Brady RO, Pan D. Platelets are efficient and protective depots for storage, distribution and delivery of lysosomal enzyme in mice with Hurler Syndrome. Proc Natl Acad Sci USA. 2014;111:2680-2685.
Wang D, El-Amouri SS, Dai M, Kuan A, Hui D, Brady RO, Pan D. Engineering a lysosomal enzyme with receptor-binding domain of ApoE enables delivery across the blood-brain barrier. Proc Natl Acad Sci U S A. 2013;110:2999-3004.
El-Amouri SS, Cao P, Miao CH, Pan D. Secreted luciferase for in vivo evaluation of systemic protein delivery in mice. Mol Biotech. 2013;53:63-73.
Pan D*, Kalfa TA, Wang D, Risinger M, Crable S, Ottlinger A, Mount DB, Hubner CA, Franco RS, Joiner CH*. KCl cotransporter gene expression during human and murine erythroid differentiation. J Biol Chem. 2011;286(35): 30492-30503. *co-correspondent authors.
Wang D, Zhang W, Kalfa TA, Grabowski G, Davies S, Malik P, Pan D. Reprogramming Erythroid Cells for Lysosomal Enzyme Production Leads to Visceral and CNS Cross-correction in Mice with Hurler Syndrome. Proc Natl Acad Sci U S A. 2009;106:19958-63.
Worsham N, Scheusler T, von Kalle C, Pan D. In vivo gene transfer into adult stem cells in non-conditioned mice by in situ delivery of a lentiviral vector. Mol Ther. 2006;14(4): 514-524.
Qishen Pang, PhD
Signal transduction in Fanconi anemia and its evolution to leukemia.
PhD: Oregon State University, Corvallis, OR, 1993.
Postdoctoral Fellow: Oregon Health Sciences University, Portland, OR, 2000.
Du W, Amarachintha S., Sipple J, Schick J., Steinbrecher K. and Pang Q. Inflammation-mediated Notch signaling skews Fanconi anemia hematopoietic stem cell differentiation. J. Immunol., 2013 Sep 1;191(5):2806-17.
Guo F, Li J, Zhang S, Du W, Sipple J, Phelan J, Grimes HL, Zheng Y, and Pang Q. mTOR kinase inhibitor sensitizes T-cell lymphoblastic leukemia for chemotherapy-induced DNA damage via suppressing FANCD2 expression. Leukemia. 2014 Jan;28(1):203-6.
Du W, Erden O, Pang Q. TNF-α signaling in Fanconi anemia. Blood Cells Mol Dis. 2014 Jan:52(1):2-11.
Guo F, Li J, Du W, Zhang S, O'Connor M, Thomas G, Kozma S, Zingarelli B, Pang Q, Zheng Y. mTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells. Leukemia. 2013 Oct:27(10):2040-6.
Shen C, Oswald D, Phelps D, Cam H, Pelloski CE, Pang Q, Houghton PJ. (2013) Regulation of FANCD2 by the mTOR Pathway Contributes to the Resistance of Cancer Cells to DNA Double-Strand Breaks. Cancer Res. 73(11):3393-401.
Guo F, Zhang S, Grogg M, Cancelas JA, Varney ME, Starczynowski DT, Du W, Yang JQ, Liu W, Zhu W, Thomas G, Kozma S, Pang Q, Zheng Y. Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis. Haematologica. 2013 Sep;98(9):1353-8.
Li X, Sipple J, Pang Q, and Du W. Salidroside stimulates DNA repair enzyme Parp-1 activity in HSC maintenance. Blood. 2012 119 4162-73.
Du W, Rani R, Sipple J, Schick J, Myers KC, Mehta P, Andreassen PA, Davies SM, and Pang Q. The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters. Blood. 2012 119(18):4142-51. 2012.
Ali AM, Pradhan A, Singh TR, Du C, Li J, Wahengbam K, Grassman E, Auerbach AD, Pang Q, Meetei AR. FAAP20: a novel ubiquitin-binding FA nuclear core complex protein required for functional integrity of the FA-BRCA DNA repair pathway. Blood. 2012 119(14):3285-94.
Li J, Sipple J, Maynard S, Mehta PA, Rose SR, Davies SM, Pang Q. Fanconi Anemia Links Reactive Oxygen Species to Insulin Resistance and Obesity. Antioxid Redox Signal. 2012 17(8):1083-98.
Nancy Ratner, PhD Beatrice C. Lampkin Chair, Cancer Biology
is working to define the interactions between glial cells and axons during nervous system development and how those interactions go awry in disease. Her goal is to develop novel therapies for patients with nervous system diseases.
Visit the Ratner Lab.
Beatrice C. Lampkin Chair, Cancer Biology
Program Leader, Cancer and Biology and Neural Tumors Program
Preclinical testing in neurofibromatosis tumors
Nancy Ratner, PhD, is interested in understanding mechanisms of peripheral nerve tumor (neurofibroma) formation in neurofibromatosis type 1 (NF1), a common inherited disorder in which children are predisposed to cancer of the nervous system, to learning problems, bone disorders, and other cancers. She identified EGFR and MEK as potential therapeutic targets in NF1 peripheral nerve tumorigenesis, and has developed cell culture and mouse models of NF1 nerve tumorigenesis. Her laboratory has also used analysis of gene expression to identify critical genes in neurofibroma and their malignant derivatives, MPNST.
Dr. Ratner received her bachelor's from Brown University, her doctorate from Indiana University, and was a postdoctoral fellow at Washington University in St. Louis. She was a member of the faculty at the University of Cincinnati from 1987 to 2004. Dr. Ratner is currently a professor in the Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, and the program leader for Cancer Biology and Neural Tumors Program in the Cancer and Blood Diseases Institute where she holds the Beatrice C. Lampkin Endowed chair in cancer biology and serves as PI of the NINDS P50 “Cincinnati Center in NF Research.”
Dr. Ratner is an active member of the International Consortium on the Molecular Biology of NF1, NF2, and Schwannomatosis and was a member of the advisory board for the National Neurofibromatosis Foundation (now Children’s Tumor Foundation) from 1989 to 2007. She chaired the Department of Defense Neurofibromatosis Research Program Integration Panel in 2008, and currently serves as a member of the James McDonnell Brain Tumor Research Advisory Board. She received the von Recklinghausen Award from the Children’s Tumor Foundation in 2010 and the Jacob K. Javits Neuroscience Investigator Award (NIH-NINDS MERIT Award) in 2014.
PhD: Indiana University, 1982.
BA: Brown University, 1975.
Fellowship: Washington University St. Louis, 1982-1987.
Mayes DA, Rizvi TA, Titus-Mitchell HA, Oberst R, Ciraolo GM, Vorhees CV, Robinson AP, Miller SD, Stemmer-Rachamimov AO, Ratner N. Nf1 loss and Ras activation in Oligodendrocytes induce NOS-driven Defects in Myelin and Vasculature. Cell Reports. 2013 Sep 26;4(6):1197-212.
Rahrmann EP, Watson AL, Keng VW, Choi K, Moriarity B, Beckmann DA, Wolf N, Sarver A, Collins MH, Moertel CL, Wallace MR, Gel B, Serra S, Ratner N, Largaespada DA. Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies novel genes and genetic pathways driving tumorigenesis. Nature Genetics. 2013;45(7):756-66.
Watson AL, Rahrmann EP, Moriarity B, Choi K, Conboy C, Greeley A, Halfond A, Anderson L, Wahl B, Keng VW, Rizzardi A, Forser C, Collins MH, Sarver A, Wallace M, Schmechel S, Ratner N, Largaespada DA. Canonical Wnt/β-catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance. Cancer Discov. 2013 Jun;3(6):674-689.
Prada CE, Jousma E, Rizvi TA, Wu J, Dunn RS, Mayes DA, Cancelas JA, Dombi E, West BL, Bollag G, Ratner N. Neurofibroma associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neurpathol. 2013;125(1):159-68.
Jessen WJ, Miller SJ, Jousma E, Rizvi TA, Eaves D, Wu J, Widemann B, Kim M-O, Dombi E, Dudley AH, Niwa-Kawakita M, Page GP, Giovannini M, Aronow BJ, Cripe TP, Ratner N. MEK Inhibition Exhibits Efficacy in Human and Mouse Neurofibromatosis Tumors Despite Transcriptional Feedback onto ERK. J Clin. Invest. 2013 Jan 2;123(1):340-7.
Patel AV, Eaves D, Jessen WJ, Rizvi TA, Ecsedy JA, Qian MG, Aronow BJ, Perentesis JP, Serra E, Cripe TP, Miller SJ, Ratner N. Ras-Driven Transcriptome Analysis Identifies Aurora Kinase A as a Potential Malignant Peripheral Nerve Sheath Tumor Therapeutic Target. Clin Canc Res. 2012 Sep 15;18(18):5020-30.
Hennigan RF, Moon CO, Parysek LM, Monk KR, Morfini G, Berth S, Brady ST, Ratner N. Merlin Modulates Microtubule-Based Vesicle Trafficking via Rac, MLK and p38SAPK. Oncogene. 2012;29(3):368-79.
Mayes DA, Rizvi TA, Cancelas JA, Kolasinski NT, Ciraolo GM, Stemmer-Rachamimov AO, Ratner N. Perinatal or Adult Nf1 Inactivation Using Tamoxifen-Inducible PlpCre Each Cause Neurofibroma Formation. Cancer Res. 2011 Jul 1;71(13):4675-85.
Hummel TR, Jessen WJ, Miller SC, Kluwe L, Mautner VF, Wallace MR, Lázaro C, Page G, Worley P, Aronow BJ, Schorry E, Ratner N. Gene expression analysis identifies potential biomarkers of neurofibromatosis type 1 including adrenomedullin. Clin Cancer Res. 2010;16 5048-57.
Miller SJ, Jessen WJ, Mehta T, Hardiman A, Sites E, Kaiser S, Jegga A, Li H, Upadhyaya M, Giovannini M, Muir D, Wallace MR, Lopez E, Serra E, Lazaro C, Stemmer-Rachamimov A, Page G, Aronow BJ, Ratner N. Integrative genomic analyses of neurofibromatosis tumors identify SOX9 as biomarker and survival gene. EMBO Mol Medicine. 2009 1(4): 236-48.
Mitogenic Activities in Neurofibromatosis. Principle Investigator. Sept 2011-2016. NIH-R01 NS 28840-20.
Preclinical Testing: GEM-Neurofibroma. Principal Investigator. Children's Tumor Foundation. Aug 2013-Jul 2016.
Identification of Neurofibroma Growth and Drug Resistance Pathways. Principal Investigator. Neurofibromatosis Therapeutic Acceleration Program (NTAP). Apr 2014-Mar 2016.
Ras Proteins in Nerve Tumorigenesis. Principal Investigator. Apr 2014-Mar 2019. 1R01 NS083580-01A1.
Novel Combinatorial Therapies for Malignant Peripheral Nerve Sheath Tumors. Co-Principal Investigator. Jul 2014-Jun 2016. 1R21NS084885-01A1.
Disordered Wnt/b-catenin signaling in MPNST Development and Maintenance. Co-Principal Investigator. Oct 2014-Sep 2019. 1R01NS086219-01A1.
Can targeted therapy prevent neurofibroma growth in mice? Principal Investigator. Neurofibromatosis Therapeutic Acceleration Program (NTAP). Sep 2014-Aug 2016.
Damien Reynaud, PhD
is an experimental hematologist interested in dissecting the cell-intrinsic and micro-environmental cues that regulate normal and pathological blood production. His research is focused on the molecular mechanisms that control normal B cell lymphopoiesis and how corruption of these mechanisms contributes to the development of acute lymphoblastic leukemia in children and adults.
Dr. Reynaud’s long-standing research interest is to understand the mechanisms controlling cell fate decisions in the hematopoietic system. During his graduate and post-graduate training, he worked to decipher the transcriptional regulatory networks that (i) control self-renewal activity and lineage specification in hematopoietic stem cells and (ii) regulate progenitor differentiation during the establishment of the natural and adaptive immune system. More recently he investigated the deregulation in stem and progenitor cell activity that, in adults, leads to the development of abnormal hematopoiesis and eventually to chronic myeloid leukemia. This work uncovered an unexpected contribution of the pro-inflammatory environment to leukemia development. Notably he identified a novel function for the pro-inflammatory cytokine IL-6 in reprogramming the fate of an early leukemic progenitor by promoting myeloid development at the expense of lymphoid differentiation. Following this work, the overall goal of his research at Cincinnati Children’s Hospital Medical Center is to characterize how micro-environmental signals regulate normal B lymphoid and how corruption of these signals contribute to the initiation, maintenance and progression of acute lymphoblastic leukemia.
PhD: University Renee Descartes, Paris, France, 2004.
Postdoctoral Fellow: University of Chicago/HHMI, Chicago, IL, 2008; University of California, San Francisco, San Francisco, CA, 2013.
Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, Debnath J, Passegué E. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature. 2013 Feb 21;494(7437):323-7.
Reynaud D*, Pietras EM, Barry-Holson K, Mir A, Binnewies M, Jeanne M, Sala-Torra O, Radich JP, Passegué E*. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell. 2011 Nov 15;20(5): 661-673. (*co-corresponding authors).
Reynaud D, Demarco IA, Reddy KL, Schjerven H, Bertolino E, Chen Z, Smale ST, Winandy S, Singh H. Regulation of B cell fate commitment and VH gene rearrangements by Ikaros. Nature Immunology. 2008 Aug; 9(8): 927-36.
Reynaud D*, Ravet E*, Titeux M, Mazurier F, Renia L, Dubart-Kupperschmitt A, Romeo PH, Pflumio F. SCL/TAL1 expression level regulates human hematopoietic stem cell self-renewal and engraftment. Blood. 2005 Oct 1;106(7): 2318-28. (*co-first author).
Ravet E*, Reynaud D*, Titeux M, Izac B, Fichelson S, Romeo PH, Dubart-Kupperschmitt A, Pflumio F. Characterization of DNA-binding dependent and independent functions of SCL/TAL1 during human erythropoiesis. Blood. 2004 May 1; 103(9): 3326-35. (*co-first author).
Reynaud D, Lefort N, Manie E, Coulombel L, Levy Y. In vitro identification of human Pro-B cells which give rise to macrophages, NK and T cells. Blood. 2003 Jun 1; 101(11): 4313-21.
Daniel T. Starczynowski, PhD
Daniel T. Starczynowski, PhD, received his PhD in molecular biology from Boston University. He studied the NF-kB family of transcription factors and their role in B-cell lymphomas. During his postdoctoral fellowship at the BC Cancer Research Center, Dr. Starczynowski identified and characterized novel candidate genes in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
Following his postdoctoral training, Dr. Starczynowski joined the faculty at Cincinnati Children’s Hospital Medical Center and at the University of Cincinnati as an assistant professor. Dr. Starczynowski’s laboratory is continuing to investigate the molecular and cellular basis of MDS. The current objective of his research program is to understand the contribution of MDS-associated miRNAs and their targeted genes to the pathogenesis of MDS and progression to AML. He hopes that understanding some of the molecular causes of MDS will enhance our insight into the biology of MDS, and provide novel targeted therapies.
BS: Fairleigh Dickinson University, Teaneck, NJ, 2000.
PhD: Boston University, Boston, MA, 2006.
Postdoctoral Fellow: University of British Columbia/BC Cancer Research Centre, Vancouver, Canada, 2010.
Varney ME, Niederkorn M, Konno H, Matsumura T, Gohda J, Yoshida N, Akiyama T, Christie S, Fang J, Miller D, Jerez A, Karsan A, Maciejewski JP, Meetei RA, Inoue J, Starczynowski DT. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J Exp Med. 2015 Oct 19;212(11):1967-85.
Varney ME, Melgar K, Niederkorn M, Smith MA, Barreyro L, Starczynowski DT. Deconstructing innate immune signaling in myelodysplastic syndromes. Exp Hematol. 2015 Aug;43(8):587-98.
Zhao JL, Starczynowski DT. Role of microRNA-146a in normal and malignant hematopoietic stem cell function. Front Genet. 2014 Jul 9;5:219.
Rhyasen GW, Wunderlich M, Tohyama K, Garcia-Manero G, Mulloy JC, Starczynowski DT. An MDS xenograft model utilizing a patient-derived cell line. Leukemia. 2014 May;28(5):1142-5.
Rhyasen GW, Bolanos L, Fang J, Jerez A, Wunderlich M, Rigolino C, Mathews L, Ferrer M, Southall N, Guha R, Keller J, Thomas C, Beverly LJ, Cortelezzi A, Oliva EN, Cuzzola M, Maciejewski JP, Mulloy JC, Starczynowski DT. Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome. Cancer Cell. 2013 Jul 8;24(1):90-104.
Fang J, Rhyasen G, Bolanos L, Rasch C, Varney M, Wunderlich M, Goyama S, Jansen G, Cloos J, Rigolino C, Cortelezzi A, Mulloy JC, Oliva EN, Cuzzola M, Starczynowski DT. Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1. Blood. 2012 Jul 26;120(4):858-67.
Starczynowski DT, Lockwood WW, Deléhouzée S, Chari R, Wegrzyn J, Fuller M, Tsao MS, Lam S, Gazdar AF, Lam WL, Karsan A. TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer. J Clin Invest. 2011 Oct;121(10):4095-105.
Starczynowski DT, Morin R, McPherson A, Lam J, Chari R, Wegrzyn J, Kuchenbauer F, Hirst M, Tohyama K, Humphries RK, Lam WL, Marra M, Karsan A. Genome-wide identification of human microRNAs located in leukemia-associated genomic alterations. Blood. 2011 Jan 13;117(2):595-607.
Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, Hirst M, Hogge D, Marra M, Wells RA, Buckstein R, Lam W, Humphries RK, Karsan A. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2010 Jan;16(1):49-58.
Ronald R. Waclaw, MS, PhD Member, Cancer Biology and Neural Tumors Program
is a developmental neurobiologist who has a research program in forebrain development and function. His lab studies the molecular genetic mechanisms in forebrain progenitor cell differentiation. One focus of his lab is to determine the effect of known “RASopathy” genes, which result in abnormalities in RAS/MAPK signaling, on brain development and brain tumor formation.
Forebrain progenitor cell differentiation; “RASopathy” genes
BA: Biology, North Central College, Naperville, IL, 1997.
MS: Department of Biology, Ball State University, Muncie, IN, 1997-1999.
PhD: Molecular and Developmental Biology, University of Cincinnati, Cincinnati, OH, 1999-2005.
Fellowship: Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 2005-2010.
Jeong Y, Dolson DK, Waclaw RR, Matise MP, Sussel L, Campbell K, Kaestner KH, Epstein DJ. Spatial and temporal requirements for sonic hedgehog in the regulation of thalamic interneuron identity. Development. 2011;138:531-541.
Waclaw RR, Ehrman LA, Pierani A, Campbell K. Developmental origin of the neuronal subtypes that comprise the amygdalar fear circuit in the mouse. J Neurosci. 2010 May 19;30(20):6944-53.
Xu Q, Guo L, Moore H, Waclaw RR, Campbell K, Anderson SA. Sonic Hedgehog confers ventral telencephalic progenitors with distinct cortical interneuron fates. Neuron. 2010 Feb;65(3):328-340.
Waclaw RR, Campbell K. Regional control of cortical lamination. Nat Neurosci. 2009 Oct;12(10):1211-2.
Waclaw RR, Wang B, Pei Z, Ehrman LA, Campbell K. Distinct temporal requirements for the homeobox gene Gsx2 in specifying striatal and olfactory bulb neuronal fates. Neuron. 2009 Aug 27;63(4):451-65.
Wang B, Waclaw RR, Allen ZJ 2nd, Guillemot F, Campbell K. Ascl1 is a required downstream effector of Gsx gene function in the embryonic mouse telencephalon. Neural Dev. 2009 Feb 10;4:5.
Allen ZJ 2nd, Waclaw RR, Colbert MC, Campbell K. Molecular identity of olfactory bulb interneurons: transcriptional codes of periglomerular neuron subtypes. J Mol Histol. 2007 Dec;38(6):517-25.
Chen L, Liao G, Waclaw RR, Burns KA, Linquist D, Campbell K, Zheng Y, Kuan CY. Rac1 controls the formation of midline commissures and the competency of tangential migration in ventral telencephalic neurons. J Neurosci. 2007 Apr 4;27(14):3884-93.
Waclaw RR, Allen ZJ 2nd, Bell SM, Erdélyi F, Szabó G, Potter SS, Campbell K. The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons. Neuron. 2006 Feb 16;49(4):503-16.
Susanne Wells, PhD Director, Epithelial Carcinogenesis and Stem Cell Program
Director, Epithelial Carcinogenesis and Stem Cell Program
Squamous cell carcinoma; mechanisms by which the HPV oncogenes subvert the host cell machinery to promote abnormal cell growth and cancer; role of specific cellular HPV targets in viral replication and cellular transformation
Visit the Wells Lab.
Susanne Wells graduated from the University of Konstanz, Germany, with a degree in biology. She completed her PhD in molecular biology at the State University of Stony Brook, NY, and her postdoctoral fellowship at Harvard Medical School, MA. Dr. Wells moved to Cincinnati Children's Hospital Medical Center in 2002 to study human papillomavirus infection and associated carcinogenesis.
Bahassi M, Li YQ, Wise-Draper TM, Deng L, Wang J, Darnell CN, Wilson KM, Wells SI, Stambrook PJ. Rixe O. A patient-derived somatic mutation in the epidural growth factor ligand-binding domain confers increased sensitivity to cetuximab in heck and neck cancer. European J Cancer. 2013 Jul:49(10):2345-55.
Privette Vinnedge LM, Ho SM. Wikenheiser-Brokamp KA, Wells SI. The DEK oncogene is a target of steroid hormone receptor signaling in breast cancer. PLoS One. 2012;7(10):e46985.
Hoskins EE, Morreale RJ, Werner SP, Higginbotham JM, Laimins LA, Lambert PF, Brown DR, Gillison ML, Nuovo GJ, Witte DP, Kim MO, Davies SM, Mehta PA, Butsch Kovacic M, Wikenheiser-Brokamp KA, Wells SI. The Fanconi anemia pathway limits human papillomavirus replication. J Virol. 2012 Aug;86(15);8131-8.
Wise-Draper TM, Draper DJ, Gutkind JS, Molinolo AA, Wikenheiser-Brokamp KA, Wells SI, Future directions and treatment strategies for head and neck squamous cell carcinomas. Transl Res. 2012 Sep;160(3):167-77.
Morrison MA, Morreale RJ, Akunuru S, Kofron M, Zheng Y, Wells SI. Targeting the human papillomavirus E6 and E7 oncogenes through expression of the BPV1 E2 protein stimulates cellular motility. J Virol. 2011 Oct;85(20):10487-98.
Myers KC, Bleesing JJ, Davies SM, Zhang X, Martin LJ, Mueller R, Harris RE, Filipovich AH, Kovacic MB, Wells SI, Mehta PA. Impaired immune function in children with Fanconi anaemia. Br J Haematol. 2011 Jul;154(2):234-40.
Kavanaugh GM, Wise-Draper TM, Morreale RJ, Morrison MA, Gole B, Schwemberger S, Tichy ED, Lu L, Babcock GF, Wells JM, Drissi R, Bissler JJ, Stambrook PJ, Andreassen PR, Wiesmuller L, Wells SI. The human DEK oncogene regulates DNA damage response signaling and repair. Nucl Acids Res. 2011 Sep 1;39(17):7465-76.
Privette Vinnedge LM, McClaine R, Wagh PK, Wikenheiser-Brokamp KA, Waltz SE, Wells SI. The human DEK oncogene stimulates β-catenin signaling, invasion and mammosphere formation in breast cancer. Oncogene. 2011 Jun 16;30:2741-52.
Spence JR, Mayhew CN, Rankin SA, Kuhar MF, Vallance JE, Toile K, Hoskins EE, Kalinichenko VV, Wells SI, Zorn AM, Shroyer NF, Wells JM. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature. 2011 Feb 3;470(733):105-9.
Meyer SE, Peace BE, Bahassi el M, Kavanaugh GM, Wagh PK, Robbins SB, Yin M,Wells SI, Zinser GM, Stambrook PJ, Waltz SE. Chk2*1100delC Acts in synergy with the Ron receptor tyrosine kinase to accelerate mammary tumorigenesis in mice. Cancer Lett. 2010 Oct 28;296(2):186-93.
Jianqiang Wu, MD, MS Member, Cancer Biology and Neural Tumors Program
focuses on preclinical therapeutic trials studying neurofibroma and cancer stem cell(s) in neurofibroma.
Preclinical therapeutic trial on neurofibroma; cancer stem cell(s) in neurofibroma
MD: Soochow University College of Medicine, SooChow, PR China, 1991.
MS: Soochow University College of Medicine, SooChow, PR China, 1996.
Wu J, Keng WV, Patmore DM, Kendall JK, Patel AV, Jousma E, Jessen WJ, Choi K, Tschida BR, Fan D, et al. Insertional mutagenesis identifies a STAT3/Arid1b/β-catenin pathway driving neurofibroma initiation. Cell Reports. 2016;14(8):1979-90.
Li H, Zhao X, Yan X, Jessen WJ, Kim M-O, Dombi E, Liu PP, Huang G, Wu J. Runx1 contributes to neurofibromatosis type1 neurofibroma formation. Oncogene. 2016;35(11):1468-74.
Wu J*, Huang G, Ratner N. Runx1: a new driver in neurofibromagenesis. Oncoscience. 2015;2(11):904-5. (*Corresponding author)
Jousma E, Rizvi TA, Wu J, Janhofer D, Dombi E, Dunn RS, Kim M, Masters AR, Jones DA, Cripe TP, Ratner N, Jousma E. Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of neurofibromatosis type 1. Pediatr Blood Cancer. 2015;62(10):1709-16.
Wu J, Patmore DM, Jousma E, Eaves DW, Schwartz EB, Fuchs JR, Cripe TP, Stemmer- Rachamimov A, Ratner N. EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors. Oncogene. 2014;33(2):173-80.
Jessen W, Miller S, Jousma E, Wu J, Rizvi T, Eaves D, Widemann B, Dombi E, Dudley A, Niwa-Kawakita M, et al. MEK Inhibition Exhibits Efficacy in Human and Mouse Neurofibromatosis Tumors. J Clin Invest. 2013;123(1):340-7.
Prada CE, Jousma E, Rizvi TA, Wu J, Dunn RS, Mayes DA, Cancelas JA, Dombi E, Kim MO, West BL, Bollag G, and Ratner N. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 2013;125(1):159-68.
Patmore DM, Welch S, Fulkerson PC, Wu J, Choi K, Eaves D, Kordich JJ, Collins MH, Cripe TP, Ratner N. In vivo regulation of TGFβ by R-Ras2 revealed through loss of the RasGAP protein Nf1. Cancer Res. 2012;72(20):5317-27.
Wu J, Williams JP, Rizvi TA, Kordich JJ, Witte D, Meijer D, Stemmer-Rachamimov AO, Cancelas JA, Ratner N. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog expressing cells. Cancer Cell. 2008;13(2):105-116.
*Williams JP, *Wu J, Johansson G, Rizvi TA, Miller SC, Geiger H, Malik P, Li W, Mukouyama YS, Cancelas JA, Ratner N. Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor population that confers tumorigenic potential. Cell Stem Cell. 2008; 3(6):658-69 (*contributed equally to the work).
Mei Xin, PhD
studies the mechanisms of heart growth, regeneration and vascular development. Dr. Xin’s research focuses on the identification and characterization of critical transcriptional and post-transcriptional molecules, as well as the signaling networks that control cardiovascular development and disease. These studies may provide insight towards therapeutic interventions for cardiovascular disorders.
Regulation of organogenesis such as cardiovascular and heart growth and regeneration, and the nervous system development
Mei Xin received her PhD from the University of Texas Southwestern Medical Center at Dallas. She completed her postdoctoral training in Eric Olson’s laboratory where she investigated microRNAs and Hippo signaling molecules regulating cardiovascular development and regeneration. In August 2013, Dr. Xin moved to Cincinnati Children’s Hospital Medical Center to study organogenesis including cardiovascular and peripheral nervous system development and diseases.
MS: Robert Wood Johnson Medical School,
PhD: The University of Texas Southwestern Medical
Center, Dallas, TX.
Fellowship: The University of Texas
Southwestern Medical Center, Dallas, TX.
Das M, Tanigawa S, Karner CM, Xin M, McNeil H, Lum L, Chen C,
Olson EN, Alan O. Perantoni AO, Carroll TJ. Stromal-epithelial crosstalk regulates kidney progenitor cell
differentiation. Nature Cell Biology.
2013 Oct 1;15(10):1260.
Xin M, Sutherland LB, Qi X, McAnally J, Richardson JA, Sadek
H., Bassel-Duby R, Olson EN. Yap Controls heart regeneration and repair. Proc
Natl Acad Sci U S A. 2013 Aug 20;110(34):13839-44.
Xin M, Bassel-Duby R and Olson EN. Cardiac Development as a Foundation for Adult Heart Regeneration and
Repair. (Invited review) Nature
Reviews Molecular Cell Biology. 2013 Aug;14(8):529-41.
Caruso P, Dempsie1 Y, Stevens H, McDonald RA, Long L, Lu R,
White K, Mair KM, Southwood M, Upton P, Xin M, van Rooij E, Olson E, Morrell NW,
MacLean MR, Baker AH. A role for miR-145
in pulmonary arterial hypertension: Evidences from mouse models and patient
samples. Circ Res. 2012 Jul
Xin M, Kim Y, Sutherland LB, Qi X, McAnally J, Schwartz RJ,
Richardson JA, Bassel-Duby R, Olson EN. Regulation
of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation
and embryonic heart size. Science
Signal. 2011 Oct 25;4(196):ra70.
Xin M, Small EM, Sutherland LB, Qi X, McAnally J, Plato CF,
Richardson JA, Bassel-Duby R, Olson EN. MicroRNAs
miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth
muscle cells to injury. Genes Dev.
2009 Sep15;23(18): 2166-78.
Xin M, Small EM,
van Rooij E, Qi X, Richardson JA, Nakagawa O, Olson EN. Essential
roles of the bHLH transcription factor Hrt2 in repression of atrial gene
expression and maintenance of postnatal cardiac function. Proc Natl Acad Sci U S A. 2007. May 8;104(19):7975-80.
Xin M, Davis CA, Molkentin JD, Lien CL, Duncan SA,
Richardson JA, Olson EN. A threshold of
GATA4 and GATA6 expression is required for cardiovascular development. Proc Natl Acad Sci U S A. 2006 Jul25;103(30):
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