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Bender, Timothy

Timothy Bender

Primary Appointment

Microbiology, Immunology, and Cancer Biology

Contact Information

Beirne Carter Center MR6-3707A
Charlottesville, VA 22908
Telephone: 434-924-1246
Fax: 434-924-1221

Research Interests

Regulation of gene expression during lymphocyte development

Research Description

The process of lymphocyte development is regulated by the complex interplay of signaling pathways and changing sets of transcription factors that are present in maturing lymphocytes. We are currently interested in the role played by the Myb family of transcription factors, particularly c-myb, in regulating T and B-lymphocyte development. Proper expression of the c-myb locus is crucial for normal adult hematopoiesis and traditional null mutations are embryonic lethal. c-myb null embryos die between day 14 and 15 of embryogenesis due to severe anemia. In addition to the crucial role played by c-myb during hematopoiesis c-myb also appears to play a significant role in the transformation of hematopoietic cells and has recently been implicated in tumors of the breast and gut epithelium as well as tumors of the nervous system. The c-myb locus encodes a highly conserved transcription factor that is highly expressed in immature hematopoietic cells and expression is turned off during the maturation of each hematopoietic lineage. During lymphocyte development, c-myb is highly expressed during the immature stages of lymphocyte development but is down regulated at or near the point of repertoire selection. Interestingly, c-myb activity increases in mature B and T lymphocytes following activation in response to antigen. Due to the embryonic lethality of the c-myb null mutation we have developed conditional mutants at the c-myb locus using the cre/loxP technology. With these mice, we are able induce deletion at the c-myb locus at specific times during lymphocyte development that allow us to study c-myb function both during antigen independent development and during differentiation of mature effector function in response to antigen. We are currently focused on determining the key points during lymphocyte development that are dependent on c-myb activity as well as the role of c-myb in regulating the population dynamics of mature B and T cell populations. In addition, these mice provide models to examine the regulation of c-myb activity by physiologically relevant signaling pathways, to determine the structural features on c-myb that are important at different times during lymphocyte development and to identify downstream effectors of c-myb function. Given the importance of appropriately regulated c-myb expression, our laboratory has been interested in determining the mechanisms that regulate c-myb expression and activity. We have demonstrated the primary mechanism that regulates expression of c-myb mRNA is a conditional block to transcription elongation (attenuation) that occurs in the first intron of the c-myb locus. We are particularly interested in characterizing signaling pathways that impact on the efficiency of this block to transcription elongation during lymphocyte development and induction of effector function. As potential targets of c-myb activity have been identified it has become apparent that c-myb is involved in the regulation of lineage and stage specific genes as well as genes that are expressed in most cell types. Thus, identifying mechanisms that regulate c-myb activity poses an interesting problem. We have identified and characterized a major site of phosphorylation on c-myb. Significantly, this site is located in a region of the c-myb protein that is deleted in transforming forms of c-myb and serves to differentially regulate c-myb on some target promoters but not others. We will examine the potential role of this phosphorylation site in activating c-myb transforming potential as well as in regulating c-myb activity during hematopoiesis. Phosphorylation does not modulate the ability of c-myb to bind DNA and we postulate that it likely regulates interaction between c-myb and other proteins that serve to modulate c-myb activity. We have identified several candidate interaction partners and are in the process of characterizing them. UNLEASH: Successful completion of at least two of the following courses is necessary to be a competitive candidate for an undergraduate research position in this lab: cell biology, genetics, biochemistry or molecular biology. Publications

Selected Publications

Gautam S, Fioravanti J, Zhu W, Le Gall JB, Brohawn P, Lacey NE, Hu J, Hocker JD, Hawk NV, Kapoor V, Telford WG, Gurusamy D, Yu Z, Bhandoola A, Xue HH, Roychoudhuri R, Higgs BW, Restifo NP, Bender TP, Ji Y, Gattinoni L, The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity., 2019; Nature immunology. 20(3) 337-349 PMID: 30778251 | PMCID: PMC6489499

Shikatani EA, Besla R, Ensan S, Upadhye A, Khyzha N, Li A, Emoto T, Chiu F, Degousee N, Moreau JM, Perry HM, Thayaparan D, Cheng HS, Pacheco S, Smyth D, Noyan H, Zavitz CCJ, Bauer CMT, Hilgendorf I, Libby P, Swirski FK, Gommerman JL, Fish JE, Stam..., c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells., 2019; Cell reports. 27(8) 2304-2312.e6 PMID: 31116977 |

Dziegielewski J, Bo?kowska MA, Poniecka EA, Heo J, Du K, Crittenden RB, Bender TP, Brautigan DL, Larner JM, Deletion of the SAPS1 subunit of protein phosphatase 6 in mice increases radiosensitivity and impairs the cellular DNA damage response., 2019; DNA repair. 85() 102737 PMID: 31751917 |

Upadhye A, Srikakulapu P, Gonen A, Hendrikx S, Perry HM, Nguyen A, McSkimming C, Marshall MA, Garmey JC, Taylor AM, Bender TP, Tsimikas S, Holodick NE, Rothstein TL, Witztum JL, McNamara CA, Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis., 2019; Circulation research. 125(10) e55-e70 PMID: 31549940 | PMCID: PMC6830526

Fahl SP, Daamen AR, Crittenden RB, Bender TP, c-Myb Coordinates Survival and the Expression of Genes That Are Critical for the Pre-BCR Checkpoint., 2018; Journal of immunology (Baltimore, Md. : 1950). 200(10) 3450-3463 PMID: 29654210 | PMCID: PMC5940554

Ziembik MA, Bender TP, Larner JM, Brautigan DL, Functions of protein phosphatase-6 in NF-?B signaling and in lymphocytes., 2017; Biochemical Society transactions. 45(3) 693-701 PMID: 28620030 | PMCID: PMC5473023

Jayappa KD, Portell CA, Gordon VL, Capaldo BJ, Bekiranov S, Axelrod MJ, Brett LK, Wulfkuhle JD, Gallagher RI, Petricoin EF, Bender TP, Williams ME, Weber MJ, Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL., 2017; Blood advances. 1(14) 933-946 PMID: 29034364 | PMCID: PMC5637393

Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J, Rajewsky N, Bender TP, Rajewsky K, MiR-150 Controls B Cell Differentiation by Targeting the Transcription Factor c-Myb., 2016; Cell. 165(4) 1027 PMID: 27153500 |

Rosenfeld SM, Perry HM, Gonen A, Prohaska TA, Srikakulapu P, Grewal S, Das D, McSkimming C, Taylor AM, Tsimikas S, Bender TP, Witztum JL, McNamara CA, B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis., 2015; Circulation research. 117(3) e28-39 PMID: 26082558 | PMCID: PMC4527334

Perry HM, Oldham SN, Fahl SP, Que X, Gonen A, Harmon DB, Tsimikas S, Witztum JL, Bender TP, McNamara CA, Helix-loop-helix factor inhibitor of differentiation 3 regulates interleukin-5 expression and B-1a B cell proliferation., 2013; Arteriosclerosis, thrombosis, and vascular biology. 33(12) 2771-9 PMID: 24115031 | PMCID: PMC4003558

Perry HM, Bender TP, McNamara CA, B cell subsets in atherosclerosis., 2012; Frontiers in immunology. 3() 373 PMID: 23248624 | PMCID: PMC3518786

Doran AC, Lipinski MJ, Oldham SN, Garmey JC, Campbell KA, Skaflen MD, Cutchins A, Lee DJ, Glover DK, Kelly KA, Galkina EV, Ley K, Witztum JL, Tsimikas S, Bender TP, McNamara CA, B-cell aortic homing and atheroprotection depend on Id3., 2011; Circulation research. 110(1) e1-12 PMID: 22034493 | PMCID: PMC3253259

Waldron T, De Dominici M, Soliera AR, Audia A, Iacobucci I, Lonetti A, Martinelli G, Zhang Y, Martinez R, Hyslop T, Bender TP, Calabretta B, c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells., 2011; Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 26(4) 644-53 PMID: 21960247 | PMCID: PMC3252490

Gimferrer I, Hu T, Simmons A, Wang C, Souabni A, Busslinger M, Bender TP, Hernandez-Hoyos G, Alberola-Ila J, Regulation of GATA-3 expression during CD4 lineage differentiation., 2011; Journal of immunology (Baltimore, Md. : 1950). 186(7) 3892-8 PMID: 21357543 | PMCID: PMC3074202

Bender TP, A new window on c-Myb function., 2010; Blood. 116(8) 1190-1 PMID: 20798239 |

Hu T, Simmons A, Yuan J, Bender TP, Alberola-Ila J, The transcription factor c-Myb primes CD4+CD8+ immature thymocytes for selection into the iNKT lineage., 2010; Nature immunology. 11(5) 435-41 PMID: 20383148 | PMCID: PMC2857587

Yuan J, Crittenden RB, Bender TP, c-Myb promotes the survival of CD4+CD8+ double-positive thymocytes through upregulation of Bcl-xL., 2010; Journal of immunology (Baltimore, Md. : 1950). 184(6) 2793-804 PMID: 20142358 | PMCID: PMC2856624

Smith E, von Vietinghoff S, Stark MA, Zarbock A, Sanders JM, Duley A, Rivera-Nieves J, Bender TP, Ley K, T-lineage cells require the thymus but not VDJ recombination to produce IL-17A and regulate granulopoiesis in vivo., 2009; Journal of immunology (Baltimore, Md. : 1950). 183(9) 5685-93 PMID: 19843951 | PMCID: PMC2893017

Fahl SP, Crittenden RB, Allman D, Bender TP, c-Myb is required for pro-B cell differentiation., 2009; Journal of immunology (Baltimore, Md. : 1950). 183(9) 5582-92 PMID: 19843942 | PMCID: PMC2785544

Giles AJ, Bender TP, Ravichandran KS, The adaptor protein Shc plays a key role during early B cell development., 2009; Journal of immunology (Baltimore, Md. : 1950). 183(9) 5468-76 PMID: 19828641 | PMCID: PMC2847786

Trampont PC, Tosello-Trampont AC, Shen Y, Duley AK, Sutherland AE, Bender TP, Littman DR, Ravichandran KS, CXCR4 acts as a costimulator during thymic beta-selection., 2009; Nature immunology. 11(2) 162-70 PMID: 20010845 | PMCID: PMC2808461

Lidonnici MR, Corradini F, Waldron T, Bender TP, Calabretta B, Requirement of c-Myb for p210(BCR/ABL)-dependent transformation of hematopoietic progenitors and leukemogenesis., 2008; Blood. 111(9) 4771-9 PMID: 18227349 | PMCID: PMC2343605

Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J, Rajewsky N, Bender TP, Rajewsky K, MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb., 2007; Cell. 131(1) 146-59 PMID: 17923094 |

Chen J, Kremer CS, Bender TP, The carbonic anhydrase I locus contains a c-Myb target promoter and modulates differentiation of murine erythroleukemia cells., 2006; Oncogene. 25(19) 2758-72 PMID: 16407849 |

Thomas MD, Kremer CS, Ravichandran KS, Rajewsky K, Bender TP, c-Myb is critical for B cell development and maintenance of follicular B cells., 2005; Immunity. 23(3) 275-86 PMID: 16169500 |

Bender TP, Kremer CS, Kraus M, Buch T, Rajewsky K, Critical functions for c-Myb at three checkpoints during thymocyte development., 2004; Nature immunology. 5(7) 721-9 PMID: 15195090 |

Zhang L, Camerini V, Bender TP, Ravichandran KS, A nonredundant role for the adapter protein Shc in thymic T cell development., 2002; Nature immunology. 3(8) 749-55 PMID: 12101399 |

Chen J, Kremer CS, Bender TP, A Myb dependent pathway maintains Friend murine erythroleukemia cells in an immature and proliferating state., 2002; Oncogene. 21(12) 1859-69 PMID: 11896618 |

Chen J, Bender TP, A novel system to identify Myb target promoters in friend murine erythroleukemia cells., 2001; Blood cells, molecules & diseases. 27(2) 429-36 PMID: 11500057 |

Allen RD, Bender TP, Siu G, c-Myb is essential for early T cell development., 1999; Genes & development. 13(9) 1073-8 PMID: 10323859 | PMCID: PMC316940

Jeng MH, Shupnik MA, Bender TP, Westin EH, Bandyopadhyay D, Kumar R, Masamura S, Santen RJ, Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells., 1998; Endocrinology. 139(10) 4164-74 PMID: 9751496 |

Miglarese MR, Richardson AF, Aziz N, Bender TP, Differential regulation of c-Myb-induced transcription activation by a phosphorylation site in the negative regulatory domain., 1996; The Journal of biological chemistry. 271(37) 22697-705 PMID: 8798443 |

Aziz N, Miglarese MR, Hendrickson RC, Shabanowitz J, Sturgill TW, Hunt DF, Bender TP, Modulation of c-Myb-induced transcription activation by a phosphorylation site near the negative regulatory domain., 1995; Proceedings of the National Academy of Sciences of the United States of America. 92(14) 6429-33 PMID: 7604007 | PMCID: PMC41531

Cuddihy AE, Brents LA, Aziz N, Bender TP, Kuehl WM, Only the DNA binding and transactivation domains of c-Myb are required to block terminal differentiation of murine erythroleukemia cells., 1993; Molecular and cellular biology. 13(6) 3505-13 PMID: 8497265 | PMCID: PMC359820

McClinton D, Stafford J, Brents L, Bender TP, Kuehl WM, Differentiation of mouse erythroleukemia cells is blocked by late up-regulation of a c-myb transgene., 1990; Molecular and cellular biology. 10(2) 705-10 PMID: 2405253 | PMCID: PMC360869

Bender TP, Thompson CB, Kuehl WM, Differential expression of c-myb mRNA in murine B lymphomas by a block to transcription elongation., 1987; Science (New York, N.Y.). 237(4821) 1473-6 PMID: 3498214 |

Bender TP, Kuehl WM, Murine myb protooncogene mRNA: cDNA sequence and evidence for 5' heterogeneity., 1986; Proceedings of the National Academy of Sciences of the United States of America. 83(10) 3204-8 PMID: 3010282 | PMCID: PMC323481