Grimes Research Lab

Our laboratory works in the fields of hematopoiesis, molecular biology, and molecular oncology including mouse modeling of hematopoiesis, myelopoiesis, marrow failure and leukemia. Our work on the Growth factor independent-1 (Gfi1) transcriptional repressor protein has spanned the initial identification of Gfi1 in a mouse model of leukemia and the role of Gfi1 in normal myeloid biology, to the identification of GFI1 mutations in patients with severe congenital neutropenia (SCN) and non-immune chronic idiopathic neutropenia of adults (NI-CINA). The Grimes laboratory has established multiple mouse models of human disease, including acute myeloid leukemia, and more recently SCN. Our work exploits these models to determine fundamental principles of development, delineate disease mechanisms, and drive toward both small-molecule and RNA therapeutics. In Nature, we utilized scRNA-Seq profiling to dissect homeostatic myeloid development and provide deep molecular insight into the process of differentiation. We are actively harnessing both established and cutting-edge single cell technologies to dissect the transcriptional and epigenetic programming of normal and malignant hematopoiesis. In collaboration with Nathan Salomonis (CCHMC) we develop biologically-centric informatics algorithms to process single cell data, web portals to disseminate the work flows, and web browsers to make the data easily accessible to biologists.

Research Grants and Contracts

  • R01CA159845 Grimes (PI) (2011-2016), “microRNA in Acute Myeloid Leukemia”
  • Children’s Leukemia Research Association (2012-2013), “Targeting Oncorequisite Factors in Leukemia”
  • Leukemia and Lymphoma Society of America Translational Research Award (2012-2015), “RNA Therapeutics for Leukemia”

Publications

For a comprehensive list of publications, visit Dr. Grimes’s My NCBI Collection in PubMed.

Olsson A, Venkatasubramanian M, Chaudhri VK, Aronow BJ, Salomonis N, Singh H, Grimes HL. Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature. 2016 Sep 29;537(7622):698-702.

Meyer SE, Qin T, Muench DE, Masuda K, Venkatasubramanian M, Orr E, Suarez L, Gore SD, Delwel R, Paietta E, Tallman MS, Fernandez H, Melnick A, Le Beau MM, Kogan S, Salomonis N, Figueroa ME, Grimes HL. DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia. Cancer Discov. 2016 May;6(5):501-15.

Velu CS, Chaubey A, Phelan JD, Horman SR, Wunderlich M, Guzman ML, Jegga AG, Zeleznik-Le NJ, Chen J, Mulloy JC, Cancelas JA, Jordan CT, Aronow BJ, Marcucci G, Bhat B, Gebelein B, Grimes HL. Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity. J Clin Invest. 2014 Jan;124(1):222-36.

Phelan JD, Saba I, Zeng H, Kosan C, Messer MS, Olsson HA, Fraszczak J, Hildeman DA, Aronow BJ, Möröy T, Grimes HL. Growth factor independent-1 maintains Notch1-dependent transcriptional programming of lymphoid precursors. PLoS Genet. 2013;9(9):e1003713.

Khandanpour C, Phelan JD, Vassen L, Schütte J, Chen R, Horman SR, Gaudreau MC, Krongold J, Zhu J, Paul WE, Dührsen U, Göttgens B, Grimes HL, Möröy T. Growth factor independence 1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia. Cancer Cell. 2013 Feb 11;23(2):200-14.

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.

Zarebski A, Velu CS, Baktula AM, Bourdeau T, Horman SR, Basu S, Bertolone SJ, Horwitz M, Hildeman DA, Trent JO, Grimes HL. Mutations in growth factor independent-1 associated with human neutropenia block murine granulopoiesis through colony stimulating factor-1. Immunity. 2008 Mar;28(3):370-80.

Kazanjian A, Wallis D, Au N, Nigam R, Venken KJ, Cagle PT, Dickey BF, Bellen HJ, Gilks CB, Grimes HL. Growth factor independence-1 is expressed in primary human neuroendocrine lung carcinomas and mediates the differentiation of murine pulmonary neuroendocrine cells. Cancer Res. 2004 Oct 1;64(19):6874-82.

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. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet. 2003 Jul;34(3):308-12.

Grimes HL, Chan TO, Zweidler-McKay PA, Tong B, Tsichlis PN. The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal. Mol Cell Biol. 1996 Nov;16(11):6263-72.

Duy C, Teater M, Garrett-Bakelman FE, Lee TC, Meydan C, Glass JL, Li M, Hellmuth JC, Mohammad HP, Smitheman KN, Shih AH, Abdel-Wahab O, Tallman MS, Guzman ML, Muench D, Grimes HL, Roboz GJ, Kruger RG, Creasy CL, Paietta EM, Levine RL, Carroll M, Melnick AM. Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML. Cancer Discov. 2019 Jul;9(7):872-889.

Adelman ER, Huang HT, Roisman A, Olsson A, Colaprico A, Qin T, Lindsley RC, Bejar R, Salomonis N, Grimes HL, Figueroa ME. Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia. Cancer Discov. 2019 May 13.

Park DS, Akuffo AA, Muench DE, Grimes HL, Epling-Burnette PK, Maini PK, Anderson ARA, Bonsall MB. Clonal hematopoiesis of indeterminate potential and its impact on patient trajectories after stem cell transplantation. PLoS Comput Biol. 2019 Apr;15(4):e1006913.

Lee C, Rudneva VA, Erkek S, Zapatka M, Chau LQ, Tacheva-Grigorova SK, Garancher A, Rusert JM, Aksoy O, Lea R, Mohammad HP, Wang J, Weiss WA, Grimes HL, Pfister SM, Northcott PA, Wechsler-Reya RJ. Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma. Nat Commun. 2019 Jan 18;10(1):332.

Dwivedi P, Muench DE, Wagner M, Azam M, Grimes HL, Greis KD. Phospho serine and threonine analysis of normal and mutated granulocyte colony stimulating factor receptors. Sci Data. 2019 Apr 9;6(1):21. PMID: 30967555.

Dwivedi P, Muench DE, Wagner M, Azam M, Grimes HL, Greis KD. Time resolved quantitative phospho-tyrosine analysis reveals Bruton's Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors. Leukemia. 2019 Jan;33(1):75-87.

Kleeman B, Olsson A, Newkold T, Kofron M, DeLay M, Hildeman DA, Grimes HL. A guide to choosing fluorescent protein combinations for flow cytometric analysis based on spectral overlap. Cytometry A. 2018 Mar 13.

Zhou Y, Yan X, Feng X, Bu J, Dong Y, Lin P, Hayashi Y, Huang R, Olsson A, Andreassen PR, Grimes HL, Wang QF, Cheng T, Xiao Z, Jin J, Huang G. Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation. Haematologica. 2018 Apr 12.

Meyer SE, Muench DE, Rogers AM, Newkold TJ, Orr E, O'Brien E, Perentesis JP, Doench JG, Lal A, Morris PJ, Thomas CJ, Lieberman J, McGlinn E, Aronow BJ, Salomonis N, Grimes HL. miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential. J Exp Med. 2018 Aug 6;215(8):2115-2136.

Zhang C, D'Alessandro A, Wellendorf AM, Mohmoud F, Serrano-Lopez J, Perentesis JP, Komurov K, Alexe G, Stegmaier K, Whitsett JA, Grimes HL, Cancelas JA. KLF5 controls glutathione metabolism to suppress p190-BCR-ABL+ B-cell lymphoblastic leukemia. Oncotarget. 2018 Jul 3;9(51):29665-29679.

Hayashi Y, Zhang Y, Yokota A, Yan X, Liu J, Choi K, Li B, Sashida G, Peng Y, Xu Z, Huang R, Zhang L, Freudiger GM, Wang J, Dong Y, Zhou Y, Wang J, Wu L, Bu J, Chen A, Zhao X, Sun X, Chetal K, Olsson A, Watanabe M, Romick-Rosendale LE, Harada H, Shih LY, Tse W, Bridges JP, Caligiuri MA, Huang T, Zheng Y, Witte DP, Wang QF, Qu CK, Salomonis N, Grimes HL, Nimer SD, Xiao Z, Huang G. Pathobiologic Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes. Cancer Discov. 2018 Nov;8(11):1438-1457.

Lu YC, Sanada C, Xavier-Ferrucio J, Wang L, Zhang PX, Grimes HL, Venkatasubramanian M, Chetal K, Aronow B, Salomonis N, Krause DS. The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification. Cell Rep. 2018 Nov 20;25(8):2083-2093.e4.

Hay S, Ferchen K, Chetal K, Grimes HL*, Salomonis N*. The Human Cell Atlas Bone Marrow Single-Cell Interactive Web Portal. Exp Hematol. 2018 Dec;68:51-61. *co-corresponding authors

Muench DE, Ferchen K, Velu CS, Pradhan K, Chetal K, Chen X, Weirauch MT, Colmenares C, Verma A, Salomonis N*, Grimes HL*. SKI controls MDS-associated chronic TGFb signaling, aberrant splicing, and stem cell fitness. Blood. 2018 Nov 22;132(21):e24-e34. NOTE: Cover of Blood. *co-corresponding authors

Lu YC, Sanada C, Xavier-Ferrucio J, Wang L, Zhang PX, Grimes HL, Venkatasubramanian M, Chetal K, Aronow B, Salomonis N, Krause DS. The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification. Cell Rep. 2018 Dec 11;25(11):3229.

Bu J, Chen A, Yan X, He F, Dong Y, Zhou Y, He J, Zhan D, Lin P, Hayashi Y, Sun Y, Zhang Y, Xiao Z, Grimes HL, Wang QF, Huang G. SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia. Leukemia. 2018 Apr;32(4):890-899.

Lee JM, Govindarajah V, Goddard B, Hinge A, Muench DE, Filippi MD, Aronow B, Cancelas JA, Salomonis N, Grimes HL, Reynaud D. Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression. J Exp Med. 2018 Feb 5;215(2):627-644.

Varney ME, Choi K, Bolanos L, Christie S, Fang J, Grimes HL, Maciejewski JP, Inoue JI, Starczynowski DT. Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome. Leukemia. 2017 Feb;31(2):491-495.

Li KP, Fähnrich A, Roy E, Cuda CM, Grimes HL, Perlman HR, Kalies K, Hildeman DA. Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCRβ Repertoire. J Immunol. 2017 Jan 1;198(1):257-269.

Rohrabaugh S, Kesarwani M, Kincaid Z, Huber E, Leddonne J, Siddiqui Z, Khalifa Y, Komurov K, Grimes HL, Azam M. Enhanced MAPK signaling is essential for CSF3R-induced leukemia. Leukemia. 2017 Jan 31.

Kesarwani M, Kincaid Z, Gomaa A, Huber E, Rohrabaugh S, Siddiqui Z, Bouso MF, Latif T, Xu M, Komurov K, Mulloy JC, Cancelas JA, Grimes HL, Azam M. Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia. Nat Med. 2017 Apr;23 (4):472-482.

Kurkewich JL, Hansen J, Klopfenstein N, Zhang H, Wood C, Boucher A, Hickman J, Muench DE, Grimes HL, Dahl R. The miR-23a~27a~24-2 microRNA cluster buffers transcription and signaling pathways during hematopoiesis. PLoS Genet. 2017 Jul 13;13(7).

Yanez A, Goodridge HS, Grimes HL. Counting the cost of lineage decisions. Nat Immunol. 2017 Jul 19;18(8):872-873.

Mizukawa B, O'Brien E, Moreira DC, Wunderlich M, Hochstetler CL, Duan X, Liu W, Orr E, Grimes HL, Mulloy JC, Zheng Y. The cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation. Blood. 2017 Sep 14;130(11):1336-1346.

Yanez A, Coetzee SG, Olsson A, Muench DE, Berman BP, Hazelett DJ, Salomonis N, Grimes HL, Goodridge HS. Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes. Immunity. 2017 Nov 21;47(5):890-902.e4.

Contact Us

A photo of Lee Grimes.

H. Leighton Grimes, PhD

Phone: 513-636-6089
Fax: 513-636-5355
Email: lee.grimes@cchmc.org

Join Our Lab

If you are interested in joining our lab, send an email to H. Leighton Grimes, PhD, at lee.grimes@cchmc.org. Include contact information and areas of research interest.