Cancer & Blood Diseases Institute

H. Leighton Grimes, PhD

Title

Director, Cancer Pathology Program of the Division of Experimental Hematology and the Division of Pathology

Appointment

Associate Professor, University of Cincinnati College of Medicine

Email

lee.grimes@cchmc.org

Phone

513-636-6089

Fax

513-636-5355

Bio

Grimes Laboratory:

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.

Division of Immunobiology

Division of Experimental Hematology and Cancer Biology

Credentials

PhD: Immunology and Molecular Pathology, University of Florida, Gainesville, FL

Postdoctoral Fellow: Fox Chase Cancer Center

Position History

Assistant Professor: University of Louisville

Associate Professor: University of Louisville

Associate Professor: Cincinnati Children's Hospital Medical Center

Research

Transcriptional control of hematopoiesis and cancer.

Research Grants and Contracts

R01 HL079574-01, NIH, NHLBI, Grimes (PI), Molecular Mechanism of Severe Congenital Neutropenia
R01 CA112405-01, NIH, NCI, Grimes (PI), A Molecular Basis for Neuroendocrine Carcinogenesis
LLS1237-06, Leukemia and Lymphoma Society Scholar, Grimes (PI), The Molecular Basis of Acute Myeloid Leukemia

Publications, Most Recent

Guo F, Velu CS, Grimes HL, and Zheng Y. Rho GTPase Cdc42 is essential for B lymphocyte development and activation. Blood 2009 “in press”.

Salipante SJ, Rojas MEB, Korkmaz B, Duan Z, Wechsler J, Benson KF, Person RE, Grimes HL, and Horwitz M. Contributions to Neutropenia from PFAAP5, a Novel Protein Mediating Transcriptional Repressor Cooperation between Gfi1 and Neutrophil Elastase. Mol Cell Biol. 2009 “in press”.

Horman SR, Velu CS, Chaubey A, Bourdeau T, Zhu J, Paul WE, Gebelein B, and Grimes HL. Gfi1 integrates progenitor versus granulocytic transcriptional programming. Blood. 2009 May 28;113(22):5466-75.

Velu CS, Baktula A, and Grimes HL. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood. 2009 May 7;113(19):4720-8.

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.

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. 2009 Apr 2;113(14):3314-22.

Montoya-Durango DE, Velu CS, Kazanjian A, Rojas ME, Jay CM, Longmore GD, Grimes HL. Ajuba functions as an HDAC-dependent co-repressor for autoregulation of the growth factor independent-1 transcription factor. J Biol Chem. 2008 Nov 14;283(46):32056-65.

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.Developmental Cell 2008;15(2):298-308.

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.

Duan Z, Person RE, Lee HH, Huang S, Donadieu J, Badolato R, Grimes HL, Papayannopoulou T, Horwitz MS. Epigenetic regulation of protein-coding and microRNA genes by the Gfi1-interacting tumor suppressor PRDM5. Mol Cell Biol. 2007 Oct;27(19):6889-902. Epub 2007 Jul 16. PMID: 17636019.

Wojciechowski S, Tripathi P, Bourdeau T, Acero L, Grimes HL, Katz JD, Finkelman FD, Hildeman DA. (2007) Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis. J Exp Med 204:1665-75.

Linnoila RI, Jensen-Taubman S, Kazanjian A, Grimes HL. (2007) Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair. Lab Invest 87:336-44.

Kazanjian A, Gross EA, Grimes HL. (2006) The growth factor independence-1 transcription factor: new functions and new insights. Crit Rev Oncol Hematol 59:85-97.

Duan Z, Zarebski A, Montoya-Durango D, Grimes HL, Horwitz M. (2005) Gfi1 coordinates epigenetic repression of p21Cip/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1. Mol Cell Biol 25:10338-51.

Dwivedi PP, Anderson PH, Omdahl JL, Grimes HL, Morris HA, May BK. (2005) Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells. Endocr Relat Cancer 12:351-65.

Park JH, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, Singer A. (2004) Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 21:289-302.

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

Huang Y, Rezzoug F, Chilton PM, Grimes HL, Cramer DE, Ildstad ST. (2004) Matching at the MHC class I K locus is essential for long-term engraftment of purified hematopoietic stem cells: a role for host NK cells in regulating HSC engraftment. Blood 104:873-80.

Grimes HL, Schanie CL, Huang Y, Cramer D, Rezzoug F, Fugier-Vivier I, Ildstad ST. (2004) Graft facilitating cells are derived from hematopoietic stem cells and functionally require CD3, but are distinct from T lymphocytes. Exp Hematol 32:946-54.

Doan LL, Porter SD, Duan Z, Flubacher MM, Montoya D, Tsichlis PN, Horwitz M, Gilks CB, Grimes HL. (2004) Targeted transcriptional repression of Gfi1 by GFI1 and GFI1B in lymphoid cells.Nucleic Acids Res 32:2508-19.

Au NH, Cheang M, Huntsman DG, Yorida E, Coldman A, Elliott WM, Bebb G, Flint J, English J, Gilks CB, Grimes HL. (2004) Evaluation of immunohistochemical markers in non-small cell lung cancer by unsupervised hierarchical clustering analysis: a tissue microarray study of 284 cases and 18 markers. J Pathol 204:101-9.

Au NH, Gown AM, Cheang M, Huntsman D, Yorida E, Elliott WM, Flint J, English J, Gilks CB, Grimes HL. (2004) P63 expression in lung carcinoma: a tissue microarray study of 408 cases. Appl Immunohistochem Mol Morphol 12:240-7.

Wallis D, Hamblen M, Zhou Y, Venken KJ, Schumacher A, Grimes HL, Zoghbi HY, Orkin SH, Bellen HJ. (2003) The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival. Development 130:221-32.

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

McGhee L, Bryan J, Elliott L, Grimes HL, Kazanjian A, Davis JN, Meyers S. (2003) Gfi-1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA-sensitive mechanism. J Cell Biochem 89:1005-18.

Doan LL, Tanner MK, Grimes HL. (2003) Intranuclear staining of proteins in heterogeneous cell populations and verification of nuclear localization by flow cytometric analysis. J Immunol Methods 279:193-8.

Doan LL, Kitay MK, Yu Q, Singer A, Herblot S, Hoang T, Bear SE, Morse HC, 3rd, Tsichlis PN, Grimes HL. (2003) Growth factor independence-1B expression leads to defects in T cell activation, IL-7 receptor alpha expression, and T cell lineage commitment. J Immunol 170:2356-66.