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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.
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 Jan;28(1):203-6. *Co-corresponding authors.
Shang X, Marchioni F, Evelyn CR, Sipes N, Zhou X, Seibel W, Wortman M, Zheng Y. Small molecule inhibitors targeting G-protein coupled Rho guanine nucleotide exchange factors. Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):3155-60.
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.
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.
Florian MC, Nattamai KJ, Dörr K, Marka G, Ueberle B, Vas V, Eckl C, Andrä I, Schiemann M, Oostendorp RA, Scharffetter-Kochanek K, Kestler HA, Zheng Y, Geiger H. A canonical to non-canonical Wnt signalling switch in hematopoietic stem cell ageing. Nature. 2013 Nov 21;503(7476):392-6.
Melendez J, Liu M, Sampson L, Akunuru S, Han X, Vallance J, Witte D, Shroyer N, Zheng Y. Cdc42 coordinates cell polarity, migration, proliferation and differentiation of the small intestinal epithelium. Gastroenterology. 2013 Oct;145(4):808-19.
Zhou X, Florian MC, Arumugam P, Chen X, Cancelas JA, Lang R, Malik P, Geiger H, Zheng Y. RhoA GTPase Controls Mitosis and Programmed Necrosis of Hematopoietic Progenitors. J Exp Med. 2013 Oct 21;210(11):2371-85.
Katayama K, Imai F, Campbell K, Lang RA, Zheng Y, Yoshida Y. RhoA and Cdc42 are required in pre-migratory progenitors of the medial ganglionic eminence ventricular zone for proper cortical interneuron migration. Development. 2013 Aug;140(15):3139-45.
Zhou X, Zheng Y. Cell type specific signaling role of RhoA GTPase: lessons from mouse gene targeting. J Biol Chem. 288(51):36179-88.
Geiger H, Zheng Y. Cdc42 and aging of hematopoietic stem cells. Curr Opin Hematol. 2013 Jul;20(4):295-300.
Targeting Cdc42 in leukemia stem cells. PI: Yi Zheng, co-PI: James Mulloy. National Cancer Institute - 1R01CA150547-01. 04/01/2010 – 03/31/2015.
Cincinnati Center of Excellence in Molecular Hematology. PI: Yi Zheng. NIDDK - NIH P30 DK090971. 09/30/2010 – 06/30/2015.
Lineage Determination and Tissue Homeostasis in the aged Hematopoietic System. PI: Yi Zheng; co-PI: Hartmut Geiger. NIA - NIH R01AG040118. 08/01/2011 – 07/31/2016.
Targeting Leukemia-associated Rho guanine nucleotide exchange factor LARG in AML. PI: Yi Zheng; co-PI: James Mulloy. Alex’s Lemonade Stand Foundation. 07/01/2013 – 06/30/2015.
Paul R. Andreassen, PhD
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
Visit the Andreassen Lab.
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
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
Structure and function analysis of tyrosine kinases involved in the pathogenesis of leukemia; molecular basis of “oncogene addiction”; modeling of human leukemia in mice using ES and patient derived iPS Cells
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
Vascular anomalies; endothelial cell biology; mTOR signaling.Visit the Boscolo Lab.
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, 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.
Jinnin M, Medici D, Park L, Limaye N, Liu Y, Boscolo E, Bischoff J, Vikkula M, Boye E, Olsen BR. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008 Nov;14(11):1236-46.
Venous Malformation (VM): murine model to identify therapies to target aberrant venous development. Principal Investigator. National Institutes of Health. 2013-2018.
Role of NOTCH signaling during pathological blood vessel formation and maturation. Principal Investigator. Charles H. Hood Foundation. 2011-2014.
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
Visit the Cancelas Lab.
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.
Progenitor Cell Biology Consortium Administrative Coordinating Center, NHLBI/ Subaward through Univ. Maryland. Co-Director. (Cincinnati Cell Char Core). Sep 2010 – Aug 2016. #U01 HL099997.
Rational Design of a Vav/Rac Inhibitor as a New Therapy for High-Risk B-ALL. Principal Investigator. Leukemia & Lymphoma Society of North America. Oct 2012 – Sep 2015.
Cincinnati Excellence in Molecular Hematology: Cell Analysis and Sorting Core, NIH/NIDDK. Co-investigator. (Flow Cytometry Core Co-PI). Sep 2010 – Jun 2015. #P30DK090971-01.
Lionel M. L. Chow, MD, PhD Member, Cancer Biology and Neural Tumors Program
Member, Cancer Biology and Neural Tumors Program
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.
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.
2013 – 2014 Sophie’s Angel Run Foundation“Preclinical Testing of Notch and mTor Inhibition in a Mouse Model for High-Grade Glioma”
2011 – 2014 St. Baldrick’s Foundation Scholars Award"Molecular targeting of pediatric high-grade glioma"
2011 – 2015 Sontag Foundation Distinguished Scientist Award"Molecular targeting of high-grade astrocytoma"
Biplab Dasgupta, PhD, MS 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. 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.
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.
Jay L. Degen, PhD
studies the mechanisms by which circulating and cell-associated hemostatic factors contribute to development, tissue reorganization, inflammatory processes and disease. He also focuses on defining the regulatory pathways by which thrombin and thrombin targets contribute to cancer biology, inflammatory joint disease, neuroinflammatory disease, bacterial virulence/host defense, and immunological disorders.
Molecular genetics of plasminogen activation in development, hemostasis, and tumor progression; molecular genetics and biological role of plasminogen activation in development, hemostasis, wound repair, and disease
Jay L. Degen, PhD, is studying the regulation and biological roles of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), the two mammalian enzymes that convert plasminogen to the active serine protease, plasmin.
The PA/plasmin system of proteases is of particular interest because of its apparent dual function in the lysis of vascular fibrin clots (fibrinolysis) and the degradation of extracellular matrix in tissue remodeling and cell migration events.
Over the last few years, Dr. Degen's lab has generated and characterized gene-targeted mouse lines with deficits in the factors that are the foundation of the coagulation and fibrinolytic cascades, including fibrinogen-, plasminogen-, plasminogen activator-, and plasminogen activator receptor-deficient mouse lines.
These unique experimental animals are being intensively analyzed with regard to a wide range of phenotypic properties, including hemostasis, wound healing, angiogenesis and tumor biology.
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.
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.
Analysis of Staphylococcus Host Interactions. Co-investigator. NIH. Sep 2010-Aug 2015. R01 AI020662.
Hartmut Geiger, PhD Director, Mouse Core
Director, Mouse Core
Hematopoietic stem cells; genetics; aging/longevity; plasticity of stem cells; mobilization; DNA-repair.
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.
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.
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.
The cloning and characterization of oncoproteins and tumor suppressors over the last 25 years has not only resulted in a greater understanding of the molecular mechanisms of transformation, but it has also provided a large set of therapeutic targets. Our lab is interested in the progression of a cell with a single genetic lesion to an invasive cancer with multiple genetic alterations. We focus on the Growth factor independence-1 (Gfi1) transcription factor, which is poorly oncogenic alone, but which potently collaborates with well known oncoproteins such as c-MYC. Gfi1 is the most frequently targeted gene in Moloney murine leukemia virus-induced tumors and induces tumor progression to cytokine-independent growth. In contrast, loss of Gfi1 in hematopoietic stem cells induces cell cycle progression and eventual bone marrow failure; implicating Gfi1 as a tumor suppressor in such cells. Gfi1 null mice have no mature neutrophils, and we have identified humans with Severe Congenital Neutropenia (SCN) and Non-Immune Chronic Idiopathic Neutropenia of Adults (NI-CINA) bearing mutations in Gfi1. Interestingly, such patients are at increased risk for the development of myelodysplastic syndromes and acute myeloid leukemia. We have recently generated the first mouse model of Severe Congenital Neutropenia through the expression of mutant Gfi1 proteins in primary murine hematopoietic cells. Moreover, we are utilizing mouse models of human cancer to assess the risk of Gfi1 mutant humans for the development of acute myeloid leukemia.
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.
Meyer SE, Hasenstein JR, Baktula A, Velu CS, Xu Y, Wan H, Whitsett JA, Gilks CB, Grimes HL. Kruppel-like factor 5 is not required for K-RasG12D lung tumorigenesis, but represses ABCG2 expression and is associated with better disease-specific survival. Am J Pathol. 2010 Sep;177(3):1503-13.
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.
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.
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
Sachin Kumar, Juying Xu, Charles Perkins, Fukun Guo, Scott Snapper, Fred D Finkelman, Yi Zheng, Marie-Dominique Filippi. Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules. Blood. 2012;120(17):3563-3574.
Juan Li, Nuyun Liu, Kangrong Lu, Lei Zhang, Jingjing Gu, Fukun Guo, Shengli An, Lin Zhang, Lu Zhang. Cocaine-induced dendritic remodeling occurs in both D1 and D2 dopamine receptor-expressing neurons in the nucleus accumbens. Neuroscience Letters. 2012;517(2):118-122.
Shuangmin Zhang, Xuan Zhou, Richard A Lang, Fukun Guo*. RhoA of the Rho family small GTPases is essential for B lymphocyte development. PLoS One. 2012.7(3):e33773 (*corresponding author).
Jessica G Woo, M Lourdes Guerrero, Fukun Guo, J Martin, Barbara S Davidson, Hilda Ortega, Guillermo M Ruiz-Palacios, Ardythe L Morrow. Human Milk Adiponectin Impacts Infant Weight Trajectory During The Second Year Of Life. Journal of Pediatric Gastroenterology & Nutrition. 2012;54(4):532-539.
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.
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.
Shang X, Cancelas JA, Li L, Guo F, Liu W, Johnson JF, Ficker A, Daria D, Geiger H, Ratner N, Zheng Y. R-Ras and Rac GTPase crosstalk regulates hematopoietic progenitor cell migration, homing and mobilization. Journal of Biological Chemistry. 2011; 286(27):24068.
Sipes NS, Feng Y, Guo F, Lee HO, Chou FS, Cheng J, Mulloy J, Zheng Y. Cdc42 regulates extracellular matrix remodeling in three dimensions. Journal of Biological Chemistry. 2011; 286(42):36469-77.
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. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18505-10.
Bosco EE, Ni W, Wang L, Guo F, Johnson JF, Zheng Y. Rac1 targeting suppresses p53 deficiency-mediated lymphomagenesis. Blood. 2010 Apr 22;115(16):3320-8.
Gang Huang, PhD
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.
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.
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.
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.
Rho GTPases in Terminal Erythroid Maturation. Principal Investigator. NIH/NHLBI. Sep 2012-Jun 2016. #1R01HL116352.
Erythrocyte Cytoskeleton Disorders Diagnostic Core. Principal Investigator. CCTST PCS T1 Pilot. July 2013- June 2015.
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
Komurov K, Ram PT. Patterns of human gene expression variance show strong associations with signaling network hierarchy. BMC Syst Biol. 2010 Nov 12;4:154. Komurov K, White MA, Ram PT. Use of data-biased random walks on graphs for the retrieval of context-specific networks from genomic data. PLoS Comput Biol. 2010 Aug 19;6(8). Taube JH*, Herschkowitz JI*, Komurov K*, Zhou AY, Gupta S, Yang J, Hartwell K, Onder TT, Gupta PB, Evans KW, Hollier BG, Ram PT, Lander ES, Rosen JM, Weinberg RA, Mani SA. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15449-54. (*Co-first author)
Komurov K, Padron D, Cheng T, Roth M, Rosenblatt KP, White MA. Comprehensive mapping of the human kinome to epidermal growth factor receptor signaling. J Biol Chem. 2010 Jul 2;285(27):21134-42. Komurov K, Gunes MH, White MA. Fine-scale dissection of functional protein network organization by statistical network analysis. PLoS One. 2009 Jun 24;4(6):e6017. Komurov K, White M. Revealing static and dynamic modular architecture of the eukaryotic protein interaction network. Mol Syst Biol. 2007;3:110.
Ashish R. Kumar, MD, PhD
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. As a faculty of the Masonic Cancer Center, he was also part of the Genetic Mechanisms of Cancer research program. 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.
Kumar AR, Yao Q, Li Q, Sam TA, Kersey JH. t(4;11) leukemias display addiction to MLL-AF4 but not to AF4-MLL. Leuk Res. 2011 Mar;35(3):305-9.
Kumar AR, Sarver AL, Wu B, Kersey JH. Meis1 maintains stemness signature in MLL-AF9 leukemia. Blood. 2010 Apr 29;115(17):3642-3.
Burke MJ, Cao Q, Trotz B, Weigel B, Kumar A, Smith A, Verneris MR. Allogeneic hematopoietic cell transplantation (allogeneic HCT) for treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer. 2009 Dec 15;53(7):1289-94.Kumar AR, Li Q, Hudson WA, Chen W, Yao Q, Sam TN, Wu B, Lund EA, Kowal BJ and Kersey JH. A role for MEIS1 in MLL-fusion gene leukemia. Blood. 2009 Feb 19; 113(8):1756-8. Chen W*, Kumar AR*, Hudson WA, Li Q, Wu B, Staggs RA, Lund EA, Sam TN and Kersey JH. Malignant transformation initiated by Mll-AF9: Gene dosage and critical target cells. Cancer Cell. 2008 May; 13: 432-440. *Co-first authors. Kris Ann P. Schultz, MD, Joseph P. Neglia, MD, MPH, Angela R. Smith, MD, Hans D. Ochs, MD, Dr. med., Troy R. Torgerson, MD, PhD, and Ashish Kumar, MD, PhD. Familial Hemophagocytic Lymphohistiocytosis in Two Brothers With X-Linked Agammaglobulinemia. Pediatric Blood and Cancer 2008; 51:293–295. White JG, Kumar AR, Hogan MJ. Gray Platelet Syndrome in a Somalian Family. Platelets. 2006 Dec; 17:519-527. Mehta PA, Davies SM, Kumar A, Devidas M, Lee S, Zamzow T, Elliott J, Villanueva J, Pullen J, Zewge Y, and Filipovich A; Children’s Oncology Group. Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia. 2006 Sep; 20; 1539-1541. Chen W, Li Q, Hudson WA, Kumar A, Kirchhof N, Kersey JH. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematological malignancy. Blood. 2006 Jul 15; 108:669-677.
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.
Instructor, UC Department of Pediatrics
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, 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.
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.
Deng Y, Kim B, He X, Kim S, Lu C, Wang H, Cho SG, Hou Y, Li J, Zhao X, Lu QR. Direct visualization of membrane architecture of myelinating cells in transgenic mice expressing membrane-anchored EGFP. Genesis. 2014;52:341-349.
Dai Z M, Sun S, Wang C, Huang H, Hu X, Zhang Z, Lu QR, Qiu M. Stage-Specific Regulation of Oligodendrocyte Development by Wnt/beta-Catenin Signaling. J Neurosci. 2014;34:8467-8473.
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.
Hennen S*, Wang H*, Peters L, Merten N, Simon K, Spinrath A, Blättermann S, Akkari R, Schrage R, Schröder R, Schulz D, Vermeiren C, Zimmermann K, Kehraus S, Drewke C, Pfeifer A, König G, Mohr K, Gillard M, Müller C, Lu QR, Gomeza J, Kostenis E. Decoding signaling and function of the orphan G protein-coupled receptor Gpr17 with a small molecule agonist. Sci Signal. 2013 Oct 22;6(298):ra93. *Co-first authors.
Limpert AS, Bai S, Narayan M, Wu J, Yoon SO, Carter BD*, Lu QR*. NF-kB forms a complex with the chromatin remodeler BRG1 to regulate Schwann cell differentiation. J Neurosci. 2013 Feb 6;33(6):2388-97. *Co-corresponding authors.
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.
Chong SY, Rosenberg SS, Fancy SP, Zhao C, Shen YA, Hahn AT, McGee AW, Xu X, Zheng B, Zhang LI, Rowitch DH, Franklin RJ, Lu QR*, Chan JR*. Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proc Natl Acad Sci U S A. 2012 Jan 24:109(4):1299-304. * Co-corresponding authors.
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.
Chen Y, Wu H, Wang S, Koito H, Li J, Ye F, Hoang J, Escobar SS, Arnett HA, Trapp BD, Karandikar NJ, Hsieh J, Lu QR. The oligodendrocyte-specific G-protein coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nat Neurosci. 2009 Nov;12(11):1398-406.
Ye F, Chen Y, Hoang T, Montgomery RL, Zhao XH, Bu H, Taketo MM, van Es JH, Clevers H, Hsieh J, Bassel-Duby R, Olson EN, Lu QR. Histone Deacetylases 1 and 2 Regulate Oligodendrocyte Differentiation By Disrupting beta-Catenin TCF Interaction. Nat Neurosci. 2009 Jul;12(7):829-38.
A Novel Model of Medulloblastoma to Define Cancer Pathways and Molecular Targets. Principal Investigator. National Institutes of Health (NINDS). April 2012 – March 2017. 1R01NS078092.
Molecular Mechanisms of Oligodendrocyte Differentiation and Myelination. Principal Investigator. National Institutes of Health (NINDS). Sept 2010 – Aug 2015. 1R01NS072427.
Chromatin Remodeling Control of CNS Myelination and Remyelination. Principal Investigator. National Institutes of Health (NINDS). April 2012 – March 2017. 1R01NS075243-01.
MicroRNA control of Myelination and Remyelination in the Central Nervous System. Principal Investigator. National Multiple Sclerosis Society. July 2012 – June 2015. RG-4727-A-6-0-1.
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
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 our lab’s major projects uses gene therapy to treat sickle cell disease. His lab is also interested in gene therapy for other diseases. He 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, Comprehensive Sickle Cell Program
Director, Translational Trials Development and Support Laboratory
Program Leader, Hematology and Gene Therapy Program
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
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.
Fanconi anemia; chromosome instability; DNA repair; multiprotein complex
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
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.
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.
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
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.
Zhao X, Chen A, Yan X, Zhang Y, He F, Hayashi Y, Dong Y, Rao Y, Li B, Conway RM, Maiques-Diaz A, Elf SE, Huang N, Zuber J, Xiao Z, Tse W, Tenen DG, Wang Q, Chen W, Mulloy JC, Nimer SD, Huang G. Down-regulation of RUNX1/CBFβ by MLL fusion proteins enhances HSC self-renewal. Blood. 2014 Mar 13;123(11):1729-38.
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. Journal of Clinical Investigation. 2014 Jan 2;124(1):222-36.
Mulloy JC. A new inducible model for t(8;21) AML. EMBO Mol Med. 2013 Dec;5(12):1795-7.
Neviani P, Harb JG, Oaks JJ, Santhanam R, Walker CJ, Ellis JJ, Ferenchak G, Paisie CA, Eiring AM, Ma Y, Mao HC, Zhang B, Wunderlich M, May PC, Sun C, Saddoughi SA, Bielawski J, Blum W, Klisovic RB, Byrd JC, Volinia S, Cortes J, Huettner CS, Koschmieder S, Holyoake TL, Devine S, Caligiuri MA, Croce CM, Garzon R, Ogretmen B, Arlinghaus RB, Chen CS, Bittman R, Hokland P, Roy DC, Milojkovic D, Apperley J, Goldman JM, Reid A, Mulloy JC, Bhatia R, Marcucci G, Perrotti D. PP2A-Activating Drugs (PADs) selectively eradicate TKI-resistant Ph+ leukemic stem cells. J Clin Invest. 2013 Oct 1;123(10):4144-4157.
Goyama S, Schibler J, Cunningham L, Zhang Y, Rao Y, Nishimoto N, Nakagawa M, Olsson A, Wunderlich M, Link KA, Mizukawa B, Grimes HL, Kurokawa M, Liu PP, Huang G, Mulloy JC. Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells. J Clin Invest. 2013 Sep 3;123(9):3876-88.
Araten DJ, Krejci O, Ditata K, Wunderlich M, Sanders KJ, Zamechek L, Mulloy JC. The rate of spontaneous mutation in human myeloid cells. Mutation Research. 2013 Sep;749(1-2):49-57.
Jiang X, Huang H, Li Z, He C, Li Y, Chen P, Gurbuxani S, Arnovitz S, Hong GM, Price C, Ren H, Kunjamma RB, Neilly MB, Salat J, Wunderlich M, Slany RK, Zhang Y, Larson RA, Le Beau MM, Mulloy JC, Rowley JD, Chen J. MiR-495 is a tumor-suppressor microRNA down-regulated in MLL-rearranged leukemia. Proc Natl Acad Sci. U S A. 2012;109(47):19397-402.
Conferring in vivo metabolic resistance to a highly selective anti-AML agent. Co-Investigator. National Institutes of Health R21 NCI (Merino/Mulloy). Apr 2014 - Mar 2016.
Origin and progression of Myelosdysplastic syndrome in patients with Bone Marrow Failure Disorders. Co-Investigator. Center for Clinical and Translational Science and Training (Mehta/Mulloy/Cancelas). Jul 2014 - Jun 2015.
Therapeutic Targeting of LARG-RhoA signaling in childhood leukemia. Co-Principal Investigator. Alex's Lemonade Stand (Zheng/Mulloy). Jul 2013 - Jun 2015.
Targeting Cdc42 in leukemia stem cells. Co-Principal Investigator. National Cancer Institute. Apr 2010 - Mar 2015. #1R01CA150547-01.
Rac Signaling in MLL Leukemia. Principal Investigator. Leukemia and Lymphoma Society. Jul 2010 - Jun 2015.
Cincinnati Center of Excellence in Molecular Hematology. Co-Director, Animal Core. National Institutes of Health. Sep 2010 – Jul 2015. # P30 DK090971.
Genotype and phenotype of chemoresistant AML. Principal Investigator. NIH, NCI. Mar 2013 - Feb 2015. R21 CA168369
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.
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
Wang D, El-Amouri SS, Dai M, Kuan A, Hui D, Brady RO and Pan D. Engineering a lysosomal enzyme with receptor-binding domain of ApoE enables delivery across the blood-brain barrier. Proc Natl Acad Sci USA, 110:2999-3004, 2013.
El-Amouri SS, Cao P, Miao CH and Pan D. Secreted luciferase for in vivo evaluation of systemic protein delivery in mice, Mol Biotech, 53:63-73, 2013.
Pan D*, Kalfa TA, Wang D, Risinger M, Crable S, Ottlinger A, Mount DB, Hubner CA, Franco RS, and Joiner CH*. KCl cotransporter gene expression during human and murine erythroid differentiation, J Biol Chem, 286(35): 30492-30503, 2011. co-correspondent authors.
Pan D. Cell- and Gene-Based Therapeutic Approaches for Neurological Deficits in Mucopolysaccharidoses. Curr Pharm Biotechnol. 2011 Jan 11.
Pan D. In situ (in vivo) gene transfer into murine bone marrow stem cells. Methods Mol Biol. 2009;506:159-69.
Wang D, Worsham DN, Pan D. Co-expression of MGMT(P140K) and alpha-L-iduronidase in primary hepatocytes from mucopolysaccharidosis type I mice enables efficient selection with metabolic correction. J Gene Med. 2008 Mar;10(3):249-59.
Pan D, Sciascia A 2nd, Vorhees CV, Williams MT. Progression of multiple behavioral deficits with various ages of onset in a murine model of Hurler syndrome. Brain Res. 2008 Jan 10;1188:241-53.
Worsham DN, Schuesler T, von Kalle C, Pan D. In vivo gene transfer into adult stem cells in unconditioned mice by in situ delivery of a lentiviral vector. Mol Ther. 2006 Oct;14(4):514-24.
Qishen Pang, PhD
Signal transduction in Fanconi anemia and its evolution to leukemia.
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.
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.
Role of FA proteins in hematopoiesis. National Institutes of Health. May 2005-Apr 2015.
Targeted improvement in stem cell therapy for leukemia and bone marrow failure syndromes. National Institutes of Health. Feb 2011-Jan 2016.
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.
Cellular and Molecular Contributors to Neurofibroma Formation. Principal Investigator. U.S. Army NF Program. Jul 2012 - Jun 2015. DOD W81XWH-11-1-0057
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
Visit the Starczynowski Lab.
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.
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.
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.
Fang J, Varney M, Starczynowski DT. Implication of miRNAs in the pathogenesis of MDS. Curr Pharm Des. 2012;18(22):3170-9.
Vercauteren S, Starczynowski DT, Sung S, McNeil K, Salski C, Jensen C-L, Lam W, Karsan A. T cells of patients with Myelodysplastic syndrome are frequently derived from the malignant clone. Br J Haematol. 2012 Feb;156(3):409-12.
Starczynowski DT, Lockwood WL, Delehouzee S, Lam S, Tsao M-S, Gazdar AF, Lam W, Karsan A. TRAF6 is an amplified oncogene bridging the Ras and nuclear factor-kB cascade in lung cancer. J Clin Invest. 2011 Oct;121(10):4095-105.
Rhyasen G, Starczynowski DT. Deregulation of microRNAs in Myelodysplastic Syndromes. Leukemia. 2011 Jan;26(1):13-22.
Kuchenbauer F, Mah SM, Heuser M, McPherson A, Ruschmann J, Rouhi A, Berg T, Bullinger L, Argiropoulos B, Morin RD, Lai D, Starczynowski DT, Karsan A, Eaves CJ, Watahiki A, Wang Y, Aparicio SA, Ganser A, Krauter J, Doehner H, Doehner K, Marra MA, Carmargo FD, Palmquist L, Buske C, Humphries RK. Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells. Blood. 2011 Sep 22;118(12):3350-8.
Starczynowski DT, Vercauteren S, Sung S, Brooks-Wilson A, Lam WL, Karsan A. Copy number alterations at polymorphic loci may be acquired somatically in patients with myelodysplastic syndromes. Leuk Res. 2011 Apr;35(4):444-7.
Starczynowski DT, Kuchenbauer F, Wegrzyn J, Humphries K, Karsan A. Increased expression of microRNA-146 disrupts differentiation and survival of hematopoietic progenitor cells. Exp Hematol. 2011 Feb;39(2):167-178.e4.
Johannes van der Loo, PhD Director, Aseptic Processing Laboratories
is director of the Aseptic Processing Laboratories, director of the Viral Vector Core and chair of the Institutional Biosafety Committee. His team continues to provide both GMP and Research-grade viral vector products to investigators locally, nationally and internationally using a fee-for-service model.
Director, Aseptic Processing Laboratories
Director, Vector Production Facility
Director, Research Viral Vector Core
Development, scale-up and clinical production of viral vectors and cellular products
Dr. van der Loo has been employed by Cincinnati Children's since 2002 where he is the Director of the Aseptic Processing Laboratories, an ISO Class 7 and 8 cleanroom facility for the manufacture of GMP-grade viral vectors and manipulation of GMP/GTP-grade cellular products for phase I/II Clinical Trials in compliance US federal and European guidelines. In addition, he is the director of the Vector Production Facility, the director of the Research Viral Vector Core and the chair of the Cincinnati Children's Institutional Biosafety Committee (IBC). His previous appointment as assistant professor (1998-2002) was with the Department of Hematology/Oncology and Transplantation, at the University of Minnesota School of Medicine, in Minneapolis, MN.
Dr. van der Loo is the director of the Cincinnati Children's Hospital Medical Center's Aseptic Processing Laboratories, Vector Production Facility and Research Viral Vector Core.
BS: Biology, State University of Utrecht, the Netherlands, 1983.
MS: Medical Biology, State University of Utrecht, the Netherlands, 1987.
Teaching degree: Biology, State University of Utrecht, Netherlands, 1989.
PhD: Hematology, Erasmus University Rotterdam, the Netherlands, 1995.
Postdoctoral Fellowship: Hematology, Howard Hughes Medical Institute, Indiana University, Indianapolis, IN, 1994-1998.
van der Loo JC, Swaney WP, Grassman E, Terwilliger A, Higashimoto T, Schambach A, Baum C, Thrasher AJ, Williams DA et al. Scale-up and manufacturing of clinical-grade self-inactivating gamma-retroviral vectors by transient transfection. Gene Ther. 2012;19(3):246-254.
van der Loo JC, Swaney WP, Grassman E, Terwilliger A, Higashimoto T, Schambach A, Baum C, Thrasher AJ, Cavazzana-Calvo M, Hacein-Bey-Abina S, Williams DA, Nordling DL, Reeves L, Malik P. Critical variables affecting clinical-grade production of the self-inactivating gamma-retroviral vector for the treatment of X-linked severe combined immunodeficiency. Gene Ther. 2012;19(8):872-876.
Schambach A, Swaney WP, van der Loo JC. Design and production of retro- and lentiviral vectors for gene expression in hematopoietic cells. Methods Mol Biol. 2009;506:191-205. Suzuki T, Sakagami T, Rubin BK, Nogee LM, Wood RE, Zimmerman SL, Smolarek T, Dishop MK, Wert SE, Whitsett JA, Grabowski G, Carey BC, Stevens C, van der Loo JC, Trapnell BC. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med. 2008 Nov 24;205(12):2703-10. Carey B, Staudt MK, Bonaminio D, van der Loo JC, Trapnell BC. PU.1 redirects adenovirus to lysosomes in alveolar macrophages, uncoupling internalization from infection. J Immunol. 2007 Feb 15;178(4):2440-7.
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
Jeong Y, Dolson DK, Waclaw RR, Matise MP, Sussel L, Campbell K, Kaestner KH, and 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
Director, Postdoctoral Office
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.
Wu J, Patmore DM, Jousma E, Eaves DW, Schwartz EB, Fuchs JR, Cripe TP, Stemmer-Rachamimov AO, Ratner N. EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors. Oncogene. 2013.
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, Dombi E, Jousma E, Dunn SR, Lindquist D, Schnell BM, Kim M , Kim A, Cripe TP, Ratner N. Preclinical testing of Sorafenib and RAD001 in the Nf1 fl/fl;DhhCre mouse model of plexiform Neurofibroma using magnetic resonance imaging. Pediatric Blood & Cancer. 2012;58(2):173-80.
Miller SJ, Lan ZD, Hardiman A, Wu J, Kordich JJ, Patmore DM, Hegde RS, Cripe TP, Cancelas JA, Collins MH, Ratner N. Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis. Oncogene. 2010;29(3):368-79.
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).
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 Biology. 2007;3:233-244.
Wu J, Crimmins JT, Monk KR, Williams JP, Fitzgerald ME, Tedesco S, Ratner N. Perinatal Epidermal Growth Factor Receptor Blockade prevents Peripheral Nerve Disruption in a Mouse Model Reminiscent of Benign World Health Organization Grade I Neurofibroma. Am J Pathol. 2006; 168(5):1686-96.
*Ling BC, *Wu J, Miller SJ, Monk KR, Shamekh R, Rizvi TA, Decourten-Myers G, Vogel KS, DeClue JE, Ratner N. Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell. 2005;7(1):65-75. Cover, (*contributed equally to the work).
Mei Xin, PhD