Utpal P. Davé, M.D.
Vanderbilt University Medical Center
2220 Pierce Ave, 777 PRB
Nashville, TN 37232-6307
Molecular genetics of leukemia and lymphoma
My lab is interested in the oncogenic pathways that are deregulated in human T-cell neoplasms. These cancers can be divided based on the cell of origin into immature, T-cell acute lymphoblastic leukemias (T-ALL) and mature, peripheral T-cell Non-Hodgkin lymphomas. In T-ALL, we are focused on understanding the function of the LIM-domain-Only-2 (LMO2) gene which is deregulated in the majority of patients. Mouse knockout studies show that Lmo2 is required for the maintenance of the hematopoietic stem cells. We hypothesize that the pathways Lmo2 regulates in stem cells may also be induced in Lmo2-associated leukemias. Experiments are ongoing to explore this idea.
Our other projects address the mechanism of mature T-cell transformation by studying HTLV-1-induced disease. HTLV-1 is a complex retrovirus that induces leukemia or lymphoma in only 5% of infected carriers after a long latency of 30-50 years. This long latency in the setting of lifelong viremia is reminiscent of the slow transforming murine leukemia viruses that we are studying in mice. Likewise, we hypothesize that insertional mutagenesis may be an active mechanism of disease induction for HTLV-1. Another project involves the role of the IL-2/IL2RG pathway in leukemia induction. We hypothesize that gain of function mutations may be occurring in genes in this pathway as tumor progression events.
Our studies will shed light on the pathogenesis of T-cell neoplasms and may provide novel targets for diagnosis or therapy.
- Cleveland, SM, Smith, S, Tripathi, R, Mathias, EM, Goodings, C, Elliott, N, Peng, D, El-Rifai, W, Yi, D, Chen, X, Li, L, Mullighan, C, Downing, JR, Love, P, Dav¿¿, UP Lmo2 induces Hematopoietic Stem Cell like Features in T-cell Progenitor Cells Prior to Leukemia. Stem Cells, 2013.
- Chmielecki, J, Peifer, M, Viale, A, Hutchinson, K, Giltnane, J, Socci, ND, Hollis, CJ, Dean, RS, Yenamandra, A, Jagasia, M, Kim, AS, DavÃ©, UP, Thomas, RK, Pao, W Systematic screen for tyrosine kinase rearrangements identifies a novel C6orf204-PDGFRB fusion in a patient with recurrent T-ALL and an associated myeloproliferative neoplasm. Genes Chromosomes Cancer, 51(1), 54-65, 2012.
- Subramaniam, PS, Whye, DW, Efimenko, E, Chen, J, Tosello, V, De Keersmaecker, K, Kashishian, A, Thompson, MA, Castillo, M, Cordon-Cardo, C, DavÃ©, UP, Ferrando, A, Lannutti, BJ, Diacovo, TG Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell, 21(4), 459-72, 2012.
- Elliott, NE, Cleveland, SM, Grann, V, Janik, J, Waldmann, TA, DavÃ©, UP FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. Blood, 118(14), 3911-21, 2011.
- Georg Aue, Yang Du, Susan M. Cleveland, Stephen B. Smith, Utpal P. DavÃ©, Delong Liu, Marc Weniger, Jean Yves Metais, Nancy A. Jenkins, Neal G. Copeland, and Cynthia E. Dunbar "Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia." Blood, in press2011.
- Aue, G, Du, Y, Cleveland, SM, Smith, SB, DavÃ©, UP, Liu, D, Weniger, MA, Metais, JY, Jenkins, NA, Copeland, NG, Dunbar, CE Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia. Blood, 118(17), 4674-81, 2011.
- Subhrajit Biswas, Qiong Shi, Lauren Matise, Susan Cleveland, Utpal Dave and Sandra Zinkel "A role for pro-apoptotic Bax and Bak in T cell differentiation and transformation." Blood, (DOI 10.1182/blood-2010-04-279687), 2010.
- Biswas, S, Shi, Q, Matise, L, Cleveland, S, Dave, U, Zinkel, S A role for proapoptotic Bax and Bak in T-cell differentiation and transformation. Blood, 116(24), 5237-46, 2010.
- Dave, UP, Akagi, K, Tripathi, R, Cleveland, SM, Thompson, MA, Yi, M, Stephens, R, Downing, JR, Jenkins, NA, Copeland, NG Murine leukemias with retroviral insertions at Lmo2 are predictive of the leukemias induced in SCID-X1 patients following retroviral gene therapy. PLoS Genet, 5(5), e1000491, 2009.
- Dave, UP Leukemia takes center (late) stage. Blood, 112(6), 2175-6, 2008.
- Dave, Utpal P. "RIS defines risk." Blood, 1101704, 2007.
- Dave, UP, Jenkins, NA, Copeland, NG Gene therapy insertional mutagenesis insights. Science, 303(5656), 333, 2004.
- Ye, J, Dave, UP, Grishin, NV, Goldstein, JL, Brown, MS Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease. Proc Natl Acad Sci U S A, 97(10), 5123-8, 2000.
- Ye, J, Rawson, RB, Komuro, R, Chen, X, Dave, UP, Prywes, R, Brown, MS, Goldstein, JL ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell, 6(6), 1355-64, 2000.
- Duncan, EA, Dave, UP, Sakai, J, Goldstein, JL, Brown, MS Second-site cleavage in sterol regulatory element-binding protein occurs at transmembrane junction as determined by cysteine panning. J Biol Chem, 273(28), 17801-9, 1998.
- M.D. - Northwestern University
- Fellowship - National Institutes of Health
- Fellowship - University of Texas Southwestern Medical Center
- Internship - University of Texas Southwestern Medical Center
- Residency - University of Texas Southwestern Medical Center