Stephen J. Brandt, M.D.

Professor

stephen.brandt@vanderbilt.edu
Faculty Appointments
Professor of Medicine Professor of Cell and Developmental BiologyProfessor of Cancer BiologyProfessor of Cancer BiologyProfessor of Cell and Developmental Biology
Education
M.D., Medicine, Emory University, Atlanta, GeorgiaB.S., Zoology, Duke University, Durham, North Carolina
Office Address
777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232-6307
2220 Pierce Avenue
Nashville, TN 37232-6307
Research Description
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.
Research Keywords
Transcriptional regulation; basic helix-loop-helix transcription factors; LIM domain proteins; protein dimerization; cell differentiation; hematopoiesis; T-cell leukemia
Publications
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 [print-electronic]. 2010 May; 30(9): 2181-92. PMID: 20194619, PMCID: PMC2863590, PII: MCB.01441-09, DOI: 10.1128/MCB.01441-09, ISSN: 1098-5549.

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. 2010; 29: 3044-53.

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 [print-electronic]. 2009 Dec 12/11/2009; 390(2): 295-301. PMID: 19799863, PMCID: PMC2774815, PII: S0006-291X(09)01928-7, DOI: 10.1016/j.bbrc.2009.09.111, ISSN: 1090-2104.

Hamid R, Brandt SJ. Transforming growth-interacting factor (TGIF) regulates proliferation and differentiation of human myeloid leukemia cells. Mol Oncol [print-electronic]. 2009 Dec; 3(5-6): 451-63. PMID: 19699159, PII: S1574-7891(09)00087-8, DOI: 10.1016/j.molonc.2009.07.004, ISSN: 1878-0261.

Brandt SJ and Koury MJ. Regulation of LMO2 mRNA and protein expression in erythroid differentiation [editorial]. Haematologica. 2009; 94: 447-8.

Brandt SJ. GATA-1: one TEF customer. Blood. 2008 Dec 12/15/2008; 112(13): 4786-7. PMID: 19064734, PII: 112/13/4786, DOI: 10.1182/blood-2008-10-181743, ISSN: 1528-0020.

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 [print-electronic]. 2008 Aug 8/22/2008; 373(2): 303-8. PMID: 18565323, PMCID: PMC2496924, PII: S0006-291X(08)01163-7, DOI: 10.1016/j.bbrc.2008.06.027, ISSN: 1090-2104.

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 [print-electronic]. 2008 May; 1779(5): 347-55. PMID: 18455519, PII: S1874-9399(08)00090-4, DOI: 10.1016/j.bbagrm.2008.04.003, ISSN: 0006-3002.

Xie J, Crooke PS, McKinney BA, Soltman J, Brandt SJ. A computational model of quantitative chromatin immunoprecipitation (ChIP) analysis. Cancer Inform [print-electronic]. 2008; 6: 138-46. PMID: 18458756, PMCID: PMC2367313, ISSN: 1176-9351.

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. 2008; 14: 7095-101.

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. 2007 Sep; 48(9): 1728-35. PMID: 17786708, PII: 781802102, DOI: 10.1080/10428190701534374, ISSN: 1042-8194.

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. 2007 Apr 4/15/2007; 21(8): 942-55. PMID: 17437998, PMCID: PMC1847712, PII: 21/8/942, DOI: 10.1101/gad.1528507, ISSN: 0890-9369.

Yang G, Thompson MA, Brandt SJ, Hiebert SW. Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein. Oncogene [print-electronic]. 2007 Jan 1/4/2007; 26(1): 91-101. PMID: 16799637, PII: 1209760, DOI: 10.1038/sj.onc.1209760, ISSN: 0950-9232.

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. 2006 Oct 10/15/2006; 399(2): 297-304. PMID: 16800816, PMCID: PMC1609906, PII: BJ20060873, DOI: 10.1042/BJ20060873, ISSN: 1470-8728.

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 [print-electronic]. 2006 Sep 9/21/2006; 25(42): 5777-86. PMID: 16652147, PII: 1209591, DOI: 10.1038/sj.onc.1209591, ISSN: 0950-9232.

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. 2006 Sep; 210(1): 121-9. PMID: 16841371, DOI: 10.1002/path.2028, ISSN: 0022-3417.

Pimanda JE, Silberstein L, Dominici M, Dekel B, Bowen M, Oldham S, Kallianpur A, Brandt SJ, Tannahill D, Gƶttgens 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. 2006 Apr; 26(7): 2615-25. PMID: 16537906, PMCID: PMC1430329, PII: 26/7/2615, DOI: 10.1128/MCB.26.7.2615-2625.2006, ISSN: 0270-7306.

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. 2006; 140: 105-19.

Linggi BE, Brandt SJ, Sun ZW, Hiebert SW. Translating the histone code into leukemia. J. Cell. Biochem. 2005 Dec 12/1/2005; 96(5): 938-50. PMID: 16167339, DOI: 10.1002/jcb.20604, ISSN: 0730-2312.

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. 2005 May; 36(5): 494-504. PMID: 15948116, PII: S0046817705001280, DOI: 10.1016/j.humpath.2005.03.004, ISSN: 0046-8177.

Wen J, Huang S, Pack SD, Yu X, Brandt SJ, Noguchi CT. Tal1/SCL binding to pericentromeric DNA represses transcription. J. Biol. Chem [print-electronic]. 2005 Apr 4/1/2005; 280(13): 12956-66. PMID: 15677454, PII: M412721200, DOI: 10.1074/jbc.M412721200, ISSN: 0021-9258.

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. 2003 Nov; 23(21): 7585-99. PMID: 14560005, PMCID: PMC207591, ISSN: 0270-7306.

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 [print-electronic]. 2002 May 5/24/2002; 277(21): 18365-72. PMID: 11904294, PII: M109812200, DOI: 10.1074/jbc.M109812200, ISSN: 0021-9258.

Koury MJ, Sawyer ST, Brandt SJ. New insights into erythropoiesis. Curr. Opin. Hematol. 2002 Mar; 9(2): 93-100. PMID: 11844990, ISSN: 1065-6251.

Stein RS, Wolff SN, Greer JP, Flexner JM, Goodman S, Jagasia M, Brandt SJ, Morgan DS, Arrowsmith E, McCurley TL. Age and cytogenetics as predictors of event free survival in patients with acute non-lymphocytic leukemia receiving high dose cytosine arabinoside and daunorubicin as consolidation chemotherapy. Leuk. Lymphoma. 2001 Sep; 42(5): 913-22. PMID: 11697646, DOI: 10.3109/10428190109097710, ISSN: 1042-8194.

Vusirikala M, Wolff SN, Stein RS, Brandt SJ, Morgan DS, Greer JP, Schuening FG, Dummer JS, Goodman SA. Valacyclovir for the prevention of cytomegalovirus infection after allogeneic stem cell transplantation: a single institution retrospective cohort analysis. Bone Marrow Transplant. 2001 Aug; 28(3): 265-70. PMID: 11535994, DOI: 10.1038/sj.bmt.1703129, ISSN: 0268-3369.

Stein RS, Greer JP, Goodman S, Brandt SJ, Morgan D, Macon WR, McCurley TL, Wolff SN. Intensified preparative regimens and allogeneic transplantation in refractory or relapsed intermediate and high grade non-Hodgkin's lymphoma. Leuk. Lymphoma. 2001 Apr; 41(3-4): 343-52. PMID: 11378547, PII: I308J001182, DOI: 10.3109/10428190109057989, ISSN: 1042-8194.

Stein RS, Greer JP, Goodman S, Brandt SJ, Morgan DS, Macon WR, McCurley TL, Wolff SN. Is total body irradiation a necessary component of preparative therapy for autologous transplantation in non-Hodgkin's lymphoma. Leuk. Lymphoma. 2001 Mar; 41(1-2): 97-103. PMID: 11342361, PII: I308J001145, DOI: 10.3109/10428190109057958, ISSN: 1042-8194.

Stein RS, Greer JP, Goodman S, Brandt SJ, Morgan DS, Macon WR, McCurley TL, Wolff SN. Limited efficacy of intensified preparative regimens and autologous transplantation as salvage therapy in high grade non-Hodgkin's lymphoma. Leuk. Lymphoma. 2001 Feb; 40(5-6): 521-8. PMID: 11426525, DOI: 10.3109/10428190109097651, ISSN: 1042-8194.

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. 2000 Dec 12/15/2000; 19(24): 6792-803. PMID: 11118214, PMCID: PMC305888, DOI: 10.1093/emboj/19.24.6792, ISSN: 0261-4189.

Huang S, Brandt SJ. MSin3A regulates murine erythroleukemia cell differentiation through association with the TAL1 (or SCL) transcription factor. Mol. Cell. Biol. 2000 Mar; 20(6): 2248-59. PMID: 10688671, PMCID: PMC110841, ISSN: 0270-7306.

Stein RS, Greer JP, Goodman S, Brandt SJ, Morgan DS, Macon WR, McCurley TL, Wolff SN. Intensified preparative regimens and autologous transplantation in refractory or relapsed intermediate grade non-Hodgkin's lymphoma. Bone Marrow Transplant. 2000 Feb; 25(3): 257-62. PMID: 10673696, DOI: 10.1038/sj.bmt.1702132, ISSN: 0268-3369.

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. 2000; 6(3A): 301-8. PMID: 10905767, ISSN: 1083-8791.

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. 1999 Nov 11/1/1999; 343 Pt 3: 615-20. PMID: 10527940, PMCID: PMC1220593, ISSN: 0264-6021.

Huang S, Qiu Y, Stein RW, Brandt SJ. P300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein. Oncogene. 1999 Sep 9/2/1999; 18(35): 4958-67. PMID: 10490830, DOI: 10.1038/sj.onc.1202889, ISSN: 0950-9232.

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. 1999 May 5/18/1999; 99(19): 2571-6. PMID: 10330390, ISSN: 0009-7322.

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. 1997 Dec 12/1/1997; 192(1): 17-30. PMID: 9405094, PII: S0012-1606(97)98751-0, DOI: 10.1006/dbio.1997.8751, ISSN: 0012-1606.

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. 1997 Jul; 6(7): 1091-8. PMID: 9215680, PMCID: PMC2871070, PII: dda134, ISSN: 0964-6906.

Prasad KS, Brandt SJ. Target-dependent effect of phosphorylation on the DNA binding activity of the TAL1/SCL oncoprotein. J. Biol. Chem. 1997 Apr 4/25/1997; 272(17): 11457-62. PMID: 9111058, ISSN: 0021-9258.

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. 1996 Jul 7/18/1996; 382(6588): 262-5. PMID: 8717042, PMCID: PMC2893578, DOI: 10.1038/382262a0, ISSN: 0028-0836.

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. 1995 May 5/12/1995; 270(19): 11603-11. PMID: 7744799, ISSN: 0021-9258.

Leelasiri A, Greer JP, Stein RS, Goodman S, Brandt SA, Edwards JR, Wolff SN. Graft-versus-host-disease prophylaxis for matched unrelated donor bone marrow transplantation: comparison between cyclosporine-methotrexate and cyclosporine-methotrexate-methylprednisolone. Bone Marrow Transplant. 1995 Mar; 15(3): 401-5. PMID: 7599565, ISSN: 0268-3369.

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. 1994 Mar 3/1/1994; 83(5): 1200-8. PMID: 8118024, ISSN: 0006-4971.

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. 1992 Jul 7/3/1992; 257(5066): 99-103. PMID: 1352414, ISSN: 0036-8075.

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. 1992; 52: 6020-4.

Brandt SJ, Bodine DM, Dunbar CE, Nienhuis AW. Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice. J. Clin. Invest. 1990 Aug; 86(2): 592-9. PMID: 2384605, PMCID: PMC296765, DOI: 10.1172/JCI114749, ISSN: 0021-9738.

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. 1990 May; 87(10): 3738-42. PMID: 2339117, PMCID: PMC53978, ISSN: 0027-8424.

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. 1990; 166: 37-41. PMID: 2073814, ISSN: 0070-217X.

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. 1989 Mar; 83(3): 921-6. PMID: 2646321, PMCID: PMC303767, DOI: 10.1172/JCI113977, ISSN: 0021-9738.

Peters WP, Atwater S, Kurtzberg J, Borowitz M, Brandt SJ, Coleman RE, Kim CS, Gilbert, C, Shpall EJ, Jones RB, Shogan J, Oette D, Stuart A, Coniglio D, Affronti ML, and Evans, S. The use of recombinant human granulocyte-macrophage colony-stimulating factor in autologous bone marrow transplantation. Bone Marrow Transplantation: Current Controversies. 1989; 595-606.

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. 1988 Aug 8/15/1988; 141(4): 1211-7. PMID: 2456345, ISSN: 0022-1767.

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. 1988 Apr 4/7/1988; 318(14): 869-76. PMID: 3281007, DOI: 10.1056/NEJM198804073181401, ISSN: 0028-4793.

Peters WP, and Brandt SJ. Granulocyte-macrophage colony-stimulating factor and marrow transplantation (letter). N Eng J Med. 1988; 319: 870-1.

Brandt SJ, Niedel JE, Bell RM, Young WS. Distinct patterns of expression of different protein kinase C mRNAs in rat tissues. Cell. 1987 Apr 4/10/1987; 49(1): 57-63. PMID: 3829128, PII: 0092-8674(87)90755-0, ISSN: 0092-8674.

Brandt SJ, Tribble CG, Lakeman AD, Hayden FG. Herpes simplex burn wound infections: epidemiology of a case cluster and responses to acyclovir therapy. Surgery. 1985 Aug; 98(2): 338-43. PMID: 4023925, ISSN: 0039-6060.

Brandt SJ, Thompson RL, Wenzel RP. Mycotic pseudoaneurysm of an aortic bypass graft and contiguous vertebral osteomyelitis due to Aspergillus fumigatus. Am. J. Med. 1985 Aug; 79(2): 259-62. PMID: 3895911, ISSN: 0002-9343.

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. 1985 May; 82(10): 3277-80. PMID: 2860668, PMCID: PMC397758, ISSN: 0027-8424.

Pember SO, Barnes KC, Brandt SJ, Kinkade JM. Density heterogeneity of neutrophilic polymorphonuclear leukocytes: gradient fractionation and relationship to chemotactic stimulation. Blood. 1983 Jun; 61(6): 1105-15. PMID: 6839018, ISSN: 0006-4971.

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. 1981 Dec; 41(12 Pt 1): 4947-51. PMID: 6272985, ISSN: 0008-5472.

Cooper RL, Brandt SJ, Linnoila M, Walker RF. Induced ovulation in aged female rats by L-dopa implants into the medial preoptic area. Neuroendocrinology. 1979; 28(4): 234-40. PMID: 571539, ISSN: 0028-3835.