Stephen J. Brandt, M.D.
Professor of Medicine, Cell and Developmental Biology, and Cancer Biology
Vanderbilt-Ingram Cancer Center
777 Preston Building
Nashville, TN 37232-6305
Our research focuses on the control of blood cell production and how this is subverted in hematologic malignancy. We have been particularly interested in the oncogene TAL1 (or SCL) that encodes a member of the helix-loop-helix family of transcription factors. Abnormal expression of this gene, originally identified through its involvement by a recurrent chromosomal translocation, constitutes the most frequent gain-of-function mutation in T-cell acute lymphoblastic leukemia (T-ALL). Many helix-loop-helix proteins are important in specification of cell fate, and studies from our lab and others indicate that TAL1 regulates fundamental aspects of hematopoietic differentiation.
We have characterized in detail the expression of TAL1 protein in murine and avian embryogenesis and, most recently, in physiological and pathological vasculogenesis. A series of studies on TAL1 function in erythroid cells have shown this transcription factor undergoes both phosphorylation and acetylation, and we have investigated its interaction with a number of transcriptional coregulators. Work is ongoing to investigate the mechanism by which misexpression of this critical regulator of normal hematopoiesis contributes to leukemic transformation and to identify both its interaction partners and downstream targets. Contemporary techniques of molecular biology and protein biochemistry and both in vitro and in vivo models are used in this research.
Leukemias; Lymphomas; Multiple Myeloma
- Wang Y, Klumpp S, Amin HM, Liang H, Li J, Estrov Z, Zweidler-McKay P, Brandt SJ, Agulnick A, and Nagarajan L "SSBP2 is an in vivo tumor suppressor and regulator of LDB1 stability." Oncogene, 293044-3053, 2010.
- Dey, S, Curtis, DJ, Jane, SM, Brandt, SJ The TAL1/SCL transcription factor regulates cell cycle progression and proliferation in differentiating murine bone marrow monocyte precursors. Mol Cell Biol, 30(9), 2181-92, 2010.
- Cai, Y, Xu, Z, Xie, J, Ham, AJ, Koury, MJ, Hiebert, SW, Brandt, SJ Eto2/MTG16 and MTGR1 are heteromeric corepressors of the TAL1/SCL transcription factor in murine erythroid progenitors. Biochem Biophys Res Commun, 390(2), 295-301, 2009.
- Brandt SJ and Koury MJ "Regulation of LMO2 mRNA and protein expression in erythroid differentiation." Haematologica, 94447-448, 2009.
- Hamid, R, Brandt, SJ Transforming growth-interacting factor (TGIF) regulates proliferation and differentiation of human myeloid leukemia cells. Mol Oncol, 3(5-6), 451-63, 2009.
- Xie, J, Crooke, PS, McKinney, BA, Soltman, J, Brandt, SJ A computational model of quantitative chromatin immunoprecipitation (ChIP) analysis. Cancer Inform, 6138-46, 2008.
- Brandt, SJ GATA-1: one TEF customer. Blood, 112(13), 4786-7, 2008.
- Hamid, R, Patterson, J, Brandt, SJ Genomic structure, alternative splicing and expression of TG-interacting factor, in human myeloid leukemia blasts and cell lines. Biochim Biophys Acta, 1779(5), 347-55, 2008.
- Cai, Y, Xu, Z, Nagarajan, L, Brandt, SJ Single-stranded DNA-binding proteins regulate the abundance and function of the LIM-homeodomain transcription factor LHX2 in pituitary cells. Biochem Biophys Res Commun, 373(2), 303-8, 2008.
- Odenike OM, Alkan S, Dorie S, Godwin JE, Huo D, Brandt SJ, Green M, Xie J, Zhang Y, Vesole DH, Stiff P, Wright J, Larson RA, Stock W, the University of Chicago Phase II Consortium "The histone deacetylase inhibitor depsipeptide has differential activity in Core Binding Factor acute myeloid leukemia." Clin. Cancer Res., 147095-7101, 2008.
- Engelhardt, BG, Holland, DW, Brandt, SJ, Chinratanalab, W, Goodman, SA, Greer, JP, Jagasia, MH, Kassim, AA, Morgan, DS, Ruffner, KL, Schuening, FG, Wolff, S, Bitting, R, Sulur, P, Stein, RS High-dose chemotherapy followed by autologous stem cell transplantation for relapsed or refractory Hodgkin lymphoma: prognostic features and outcomes. Leuk Lymphoma, 48(9), 1728-35, 2007.
- Yang, G, Thompson, MA, Brandt, SJ, Hiebert, SW Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein. Oncogene, 26(1), 91-101, 2007.
- Xu, Z, Meng, X, Cai, Y, Liang, H, Nagarajan, L, Brandt, SJ Single-stranded DNA-binding proteins regulate the abundance of LIM domain and LIM domain-binding proteins. Genes Dev, 21(8), 942-55, 2007.
- Tang, T, Shi, Y, Opalenik, SR, Brantley-Sieders, DM, Chen, J, Davidson, JM, Brandt, SJ Expression of the TAL1/SCL transcription factor in physiological and pathological vascular processes. J Pathol, 210(1), 121-9, 2006.
- Reed-Inderbitzin, E, Moreno-Miralles, I, Vanden-Eynden, SK, Xie, J, Lutterbach, B, Durst-Goodwin, KL, Luce, KS, Irvin, BJ, Cleary, ML, Brandt, SJ, Hiebert, SW RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription. Oncogene, 255777-5786, 2006.
- Xu, Z, Meng, X, Cai, Y, Koury, MJ, Brandt, SJ Recruitment of the SWI/SNF protein Brg1 by a multiprotein complex effects transcriptional repression in murine erythroid progenitors. Biochem J, 399(2), 297-304, 2006.
- Tran YH, Xu Z, Kato A, Mistry AC, Goya Y, Taira M, Brandt SJ, and Hirose S "Spliced isoforms of LIM-domain-binding protein (CLIM/NLI/Ldb) lacking LIM-interaction domain." J. Biochem., 140105-119, 2006.
- Pimanda, JE, Silberstein, L, Dominici, M, Dekel, B, Bowen, M, Oldham, S, Kallianpur, A, Brandt, SJ, Tannahill, D, GÃ¶ttgens, B, Green, AR Transcriptional link between blood and bone: the stem cell leukemia gene and its +19 stem cell enhancer are active in bone cells. Mol Cell Biol, 26(7), 2615-25, 2006.
- Thompson, MA, Stumph, J, Henrickson, SE, Rosenwald, A, Wang, Q, Olson, S, Brandt, SJ, Roberts, J, Zhang, X, Shyr, Y, Kinney, MC Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas. Hum Pathol, 36(5), 494-504, 2005.
- Wen, J, Huang, S, Pack, SD, Yu Y, Brandt, SJ, Noguchi, CT Tal1/SCL binding to pericentromeric DNA represses transcription. J Biol Chem, 280(13), 12956-66, 2005.
- Linggi, BE, Brandt, SJ, Sun, ZW, Hiebert, SW Translating the histone code into leukemia. J Cell Biochem, 96(5), 938-50, 2005.
- Xu, Z, Huang, S, Chang, LS, Agulnick, AD, Brandt, SJ Identification of a TAL1 target gene reveals a positive role for the LIM domain-binding protein Ldb1 in erythroid gene expression and differentiation. Mol Cell Biol, 23(21), 7585-99, 2003.
- Koury, MJ, Sawyer, ST, Brandt, SJ New insights into erythropoiesis. Curr Opin Hematol, 9(2), 93-100, 2002.
- Tang, T, Arbiser, JL, Brandt, SJ Phosphorylation by mitogen-activated protein kinase mediates the hypoxia-induced turnover of the TAL1/SCL transcription factor in endothelial cells. J Biol Chem, 277(21), 18365-72, 2002.
- Ikpeazu, C, Davidson, MK, Halteman, D, Browning, PJ, Brandt, SJ Donor origin of circulating endothelial progenitors after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant, 6(3A), 301-8, 2000.
- Huang, S, Qiu, Y, Shi, Y, Xu, Z, Brandt, SJ P/CAF-mediated acetylation regulates the function of the basic helix-loop-helix transcription factor TAL1/SCL. EMBO J, 19(24), 6792-803, 2000.
- Huang, S, Brandt, SJ mSin3A regulates murine erythroleukemia cell differentiation through association with the TAL1 (or SCL) transcription factor. Mol Cell Biol, 20(6), 2248-59, 2000.
- Tang, T, Prasad, KS, Koury, MJ, Brandt, SJ Mitogen-activated protein kinase mediates erythropoietin-induced phosphorylation of the TAL1/SCL transcription factor in murine proerythroblasts. Biochem J, 343 Pt 3615-20, 1999.
- Hasty, AH, Linton, MF, Brandt, SJ, Babaev, VR, Gleaves, LA, Fazio, S Retroviral gene therapy in ApoE-deficient mice: ApoE expression in the artery wall reduces early foam cell lesion formation. Circulation, 99(19), 2571-6, 1999.
- Huang, S, Qiu, Y, Stein, RW, Brandt, SJ p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein. Oncogene, 18(35), 4958-67, 1999.
- Barbosa, MD, Barrat, FJ, Tchernev, VT, Nguyen, QA, Mishra, VS, Colman, SD, Pastural, E, Dufourcq-Lagelouse, R, Fischer, A, Holcombe, RF, Wallace, MR, Brandt, SJ, de Saint Basile, G, Kingsmore, SF Identification of mutations in two major mRNA isoforms of the Chediak-Higashi syndrome gene in human and mouse. Hum Mol Genet, 6(7), 1091-8, 1997.
- Drake, CJ, Brandt, SJ, Trusk, TC, Little, CD TAL1/SCL is expressed in endothelial progenitor cells/angioblasts and defines a dorsal-to-ventral gradient of vasculogenesis. Dev Biol, 192(1), 17-30, 1997.
- Prasad, KS, Brandt, SJ Target-dependent effect of phosphorylation on the DNA binding activity of the TAL1/SCL oncoprotein. J Biol Chem, 272(17), 11457-62, 1997.
- Barbosa, MD, Nguyen, QA, Tchernev, VT, Ashley, JA, Detter, JC, Blaydes, SM, Brandt, SJ, Chotai, D, Hodgman, C, Solari, RC, Lovett, M, Kingsmore, SF Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature, 382(6588), 262-5, 1996.
- Prasad, KS, Jordan, JE, Koury, MJ, Bondurant, MC, Brandt, SJ Erythropoietin stimulates transcription of the TAL1/SCL gene and phosphorylation of its protein products. J Biol Chem, 270(19), 11603-11, 1995.
- Kallianpur, AR, Jordan, JE, Brandt, SJ The SCL/TAL-1 gene is expressed in progenitors of both the hematopoietic and vascular systems during embryogenesis. Blood, 83(5), 1200-8, 1994.
- Mullen CA, Coale MM, Levy AT, Stetler-Stevenson WG, Liotta LA, Brandt S, and Blaese RM "Fibrosarcoma cells transduced with the IL-6 gene exhibit reduced tumorigenicity, increased immunogenicity and decreased metastatic potential." Cancer Research, 526020-6024, 1992.
- Sorrentino, BP, Brandt, SJ, Bodine, D, Gottesman, M, Pastan, I, Cline, A, Nienhuis, AW Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1. Science, 257(5066), 99-103, 1992.
- Bodine, DM, McDonagh, KT, Brandt, SJ, Ney, PA, Agricola, B, Byrne, E, Nienhuis, AW Development of a high-titer retrovirus producer cell line capable of gene transfer into rhesus monkey hematopoietic stem cells. Proc Natl Acad Sci U S A, 87(10), 3738-42, 1990.
- Brandt, SJ, Bodine, DM, Dunbar, CE, Nienhuis, AW Dysregulated interleukin 6 expression produces a syndrome resembling Castleman''s disease in mice. J Clin Invest, 86(2), 592-9, 1990.
- Brandt, SJ, Bodine, DM, Dunbar, CE, Nienhuis, AW Retroviral-mediated transfer of interleukin-6 into hematopoietic cells of mice results in a syndrome resembling Castleman''s disease. Curr Top Microbiol Immunol, 16637-41, 1990.
- Ramakrishnan, S, Xu, FJ, Brandt, SJ, Niedel, JE, Bast, RC, Brown, EL Constitutive production of macrophage colony-stimulating factor by human ovarian and breast cancer cell lines. J Clin Invest, 83(3), 921-6, 1989.
- Brandt, SJ, Peters, WP, Atwater, SK, Kurtzberg, J, Borowitz, MJ, Jones, RB, Shpall, EJ, Bast, RC, Gilbert, CJ, Oette, DH Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation. N Engl J Med, 318(14), 869-76, 1988.
- Le, PT, Kurtzberg, J, Brandt, SJ, Niedel, JE, Haynes, BF, Singer, KH Human thymic epithelial cells produce granulocyte and macrophage colony-stimulating factors. J Immunol, 141(4), 1211-7, 1988.
- Brandt, SJ, Niedel, JE, Bell, RM, Young, WS Distinct patterns of expression of different protein kinase C mRNAs in rat tissues. Cell, 49(1), 57-63, 1987.
- Brandt, SJ, Dougherty, RW, Lapetina, EG, Niedel, JE Pertussis toxin inhibits chemotactic peptide-stimulated generation of inositol phosphates and lysosomal enzyme secretion in human leukemic (HL-60) cells. Proc Natl Acad Sci U S A, 82(10), 3277-80, 1985.
- Pember, SO, Barnes, KC, Brandt, SJ, Kinkade, JM Density heterogeneity of neutrophilic polymorphonuclear leukocytes: gradient fractionation and relationship to chemotactic stimulation. Blood, 61(6), 1105-15, 1983.
- Brandt, SJ, Barnes, KC, Glass, DB, Kinkade, JM Glucocorticoid-stimulated increase in chemotactic peptide receptors on differentiating human myeloid leukemia (HL-60) cells. Cancer Res, 41(12 Pt 1), 4947-51, 1981.