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Our laboratory works in the fields of hematopoiesis, molecular biology, and molecular oncology including mouse modeling of hematopoiesis, myelopoiesis 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). We have identified Csf1, miR-21 and miR-196b as functional targets of Gfi1 that control the SCN-associated Gfi1-mutant block to granulopoiesis. Recently, we have illustrated an ancient Gfi1 versus HoxA9-Pbx1-Meis1 transcriptional circuit present from Drosophila anterior-posterior development to myeloid progenitor maintenance and transformation. Notably, HoxA9, Meis1 and Pbx1 are three key factors widely acknowledged to drive acute myeloid leukemia; however, their critical target genes are relatively obscure. We are now focused on the antagonism between Gfi1 and the HoxA9-Pbx1-Meis1 oncoproteins in myeloid progenitors, where we find that they fight over the regulation of miR-21 and miR-196b. These miR are critically required for Hox-based myeloid transformation. Our latest data provide evidence for an RNA therapeutic modality that efficiently and specifically interferes with miR-21 and miR-196b function in vivo, resulting in significant changes in the survival of mice bearing Hox-based leukemias. Finally, we are also dissecting the role of Gfi1 in controlling the normal process of granulopoiesis.
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. In press.
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. 2013 Jul 15. doi: 10.1038/leu.2013.215. [Epub ahead of print]
Raines AM, Adam M, Magella B, Meyer SE, Grimes HL, Dey SK, Potter SS. Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts.Development. 2013 Jul;140(14):2942-52. doi: 10.1242/dev.092569. Epub 2013 Jun 12.
Taniguchi Ishikawa E, Chang KH, Nayak R, Olsson HA, Ficker AM, Dunn SK, Madhu MN, Sengupta A, Whitsett JA, Grimes HL, Cancelas JA. Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking.Nat Commun. 2013;4:1660. doi: 10.1038/ncomms2645.
Horwitz MS, Corey SJ, Grimes HL, Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology.Hematol Oncol Clin North Am. 2013 Feb;27(1):19-41, vii. doi: 10.1016/j.hoc.2012.10.004. Epub 2012 Nov 7. Review.
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. doi: 10.1016/j.ccr.2013.01.011. PMID: 23410974 *Equal first author, #shared corresponding authors.
Velu CS and Grimes HL. Utilizing Antagomir (Antisense microRNA) to Knock Down microRNA in Murine Bone Marrow Cells. Chapter 15, Rational Drug Design, Methods in Molecular Biology, 2012, Vol 928, p185-95. PMID: 22956143
Unnisa Z, Clark JP, Roychoudhury J, Thomas E, Tessarollo L, Copeland NG, Jenkins NA, Grimes HL, Kumar AR. Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress. Blood. 2012 Dec 13;120(25):4973-81. PMID: 23091297
Khandanpour C, Krongold J, Schütte J, Bouwman F, Vassen L, Gaudreau MC, Chen R, Calero-Nieto FJ, Diamanti E, Hannah R, Meyer SE, Grimes HL, van der Reijden BA, Jansen JH, Patel CV, Peeters JK, Löwenberg B, Dührsen U, Göttgens B, Möröy T. The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice. Blood. 2012 Nov 8;120(19):4006-17. PMID: 22932805
Zhang Y, Yan X, Sashida G, Zhao X, Rao Y, Goyama S, Whitman SP, Zorko N, Bernot K, Conway RM, Witte D, Wang QF, Tenen DG, Xiao Z, Marcucci G, Mulloy JC, Grimes HL, Caligiuri MA, Huang G. Stress hematopoiesis reveals abnormal control of self-renewal, lineage-bias and myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic stem/progenitor cells. Blood. 2012 Aug 2;120(5):1118-29. PMID: 22740449
Barger JF, Gallo CA, Tandon P, Liu H, Sullivan A, Grimes HL, Plas DR., S6K1 determines the metabolic requirements for BCR-ABL survival. Oncogene. 2012 Mar 5. In press. PMID: 22391570
D’Souza S, del Prete D, Jin S, Sun Q, Huston AJ, Esteve F, Sammut B, Hong CS, Anderson JL, Patrene KD, Yu S, Velu CS, Xiao G, Grimes HL, Roodman GD, Galson DL. Gfi1 Expressed in Bone Marrow Stromal Cells Is a Novel Osteoblast Suppressor in Patients With Multiple Myeloma Bone Disease. Blood. 2011.
McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and p53 Cooperate to Prevent Liver Tumorigenesis in Response to Tissue Damage. Gastroenterology. 2011 Jun 23.
Stoffers SL, Meyer SE, Grimes HL. MicroRNAs in the midst of myeloid signal transduction. J Cell Physiol. 2011 May 12.
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. 6(3):e18002. Mar 24, 2011.
Kurtulus S, Tripathi P, Moreno-Fernandez ME, Sholl A, Katz JD, Grimes HL, Hildeman DA. Bcl-2 Allows Effector and Memory CD8+ T Cells To Tolerate Higher Expression of Bim. J Immunol. Mar 30, 2011.
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. 107(43):18505-10. Oct 26, 2010.
Tripathi P, Kurtulus S, Wojciechowski S, Sholl A, Hoebe K, Morris SC, Finkelman FD, Grimes HL, Hildeman DA. STAT5 is critical to maintain effector CD8+ T cell responses. J Immunol. 185(4):2116-24. Aug 15, 2010.
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. 177(3):1503-13. Sep, 2010.
Phelan JD, Shroyer NF, Cook T, Gebelein B, Grimes HL. Gfi1-cells and circuits: unraveling transcriptional networks of development and disease. Curr Opin Hematol. 17(4):300-7. Jul, 2010.
Sharif-Askari E, Vassen L, Kosan C, Khandanpour C, Gaudreau MC, Heyd F, Okayama T, Jin J, Rojas ME, Grimes HL, Zeng H, Möröy T. Zinc finger protein Gfi1 controls the endotoxin-mediated Toll-like receptor inflammatory response by antagonizing NF-kappaB p65. Mol Cell Biol. 30(16):3929-42. Aug 30, 2010.
Kong KY, Owens KS, Rogers JH, Mullenix J, Velu CS, Grimes HL, Dahl R. MIR-23A microRNA cluster inhibits B-cell development. Exp Hematol. 38(8):629-640.e1. Aug, 2010.
Barnes MJ, Aksoylar H, Krebs P, Bourdeau T, Arnold CN, Xia Y, Khovananth K, Engel I, Sovath S, Lampe K, Laws E, Saunders A, Butcher GW, Kronenberg M, Steinbrecher K, Hildeman D, Grimes HL, Beutler B, Hoebe K. Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. J Immunol. 184(7):3743-54. Apr 1, 2010.
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. 4(9):e6995. Sep 10, 2009.
Guo F, Velu CS, Grimes HL, Zheng Y. Rho GTPase Cdc42 is essential for B-lymphocyte development and activation. Blood. 114(14):2909-16. Oct 1, 2009.
Salipante SJ, Rojas ME, Korkmaz B, Duan Z, Wechsler J, Benson KF, Person RE, Grimes HL, Horwitz MS. Contributions to neutropenia from PFAAP5 (N4BP2L2), a novel protein mediating transcriptional repressor cooperation between Gfi1 and neutrophil elastase. Mol Cell Biol. 29(16):4394-405. Aug, 2009.
Horman SR, Velu CS, Chaubey A, Bourdeau T, Zhu J, Paul WE, Gebelein B, Grimes HL. Gfi1 integrates progenitor versus granulocytic transcriptional programming. Blood. 113(22):5466-75. May 28, 2009.
Velu CS, Baktula AM, Grimes HL. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood. 113(19):4720-8. May 7, 2009.
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. 458(7241):1039-42. Apr 23, 2009.
Popovic R, Riesbeck LE, Velu CS, Chaubey A, Zhang J, Achille NJ, Erfurth FE, Eaton K, Lu J, Grimes HL, Chen J, Rowley JD, Zeleznik-Le NJ. Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood. 113(14):3314-22. Apr 2, 2009.
Montoya-Durango DE, Velu CS, Kazanjian A, Rojas ME, Jay CM, Longmore GD, Grimes HL. Ajuba functions as a histone deacetylase-dependent co-repressor for autoregulation of the growth factor-independent-1 transcription factor. J Biol Chem. 283(46):32056-65. Nov 14, 2008.
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. 15(2):298-308. Aug 15, 2008.
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. 28(3):370-80. Mar, 2008.
H. Leighton Grimes, PhD
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