Timothy P. Bender


Primary Appointment

, Microbiology, Immunology, and Cancer Biology


  • BA, Biology, Albion College
  • MS, Epidemiology, The University of Michigan, Ann Arbor, MI
  • PhD, Microbiology and Immunology, The University of Michigan, Ann Arbor, MI

Research Disciplines

Bioinformatics and Genomics, Cancer Biology, Epigenetics, Genetics, Immunology, Infectious Diseases/Biodefense, Microbiology, Molecular Biology

Research Interests

c-Myb and B-cell development

Personal Statement

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 do 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 a 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
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.


  • Biodefense & Infectious Diseases Short-Term Training to Increase Diversity in Biomedical Sciences

Selected Publications


Yao, M., Ventura, P. B., Jiang, Y., Rodriguez, F. J., Wang, L., Perry, J. S. A., . . . Zong, H. (2020). Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth. CELL, 180(3), 502-+. doi:10.1016/j.cell.2019.12.024

Dziegielewski, J., Bonkowska, M. A., Poniecka, E. A., Heo, J., Du, K., Crittenden, R. B., . . . Larner, J. M. (2020). Deletion of the SAPS1 subunit of protein phosphatase 6 in mice increases radiosensitivity and impairs the cellular DNA damage response. DNA REPAIR, 85. doi:10.1016/j.dnarep.2019.102737


Upadhye, A., Srikakulapu, P., Gonen, A., Hendrikx, S., Perry, H. M., Nguyen, A., . . . McNamara, C. A. (2019). Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis. CIRCULATION RESEARCH, 125(10), E55-E70. doi:10.1161/CIRCRESAHA.119.315786

Shikatani, E. A., Besla, R., Ensan, S., Upadhye, A., Khyzha, N., Li, A., . . . Robbins, C. S. (2019). c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells. CELL REPORTS, 27(8), 2304-+. doi:10.1016/j.celrep.2019.04.090

Gautam, S., Fioravanti, J., Zhu, W., Le Gall, J. B., Brohawn, P., Lacey, N. E., . . . Gattinoni, L. (2019). The transcription factor c-Myb regulates CD8(+) T cell stemness and antitumor immunity. NATURE IMMUNOLOGY, 20(3), 337-+. doi:10.1038/s41590-018-0311-z


Fahl, S. P., Daamen, A. R., Crittenden, R. B., & Bender, T. P. (2018). c-Myb Coordinates Survival and the Expression of Genes That Are Critical for the Pre-BCR Checkpoint. JOURNAL OF IMMUNOLOGY, 200(10), 3450-3463. doi:10.4049/jimmunol.1302303


Tang, F., Zhang, P., Ye, P., Lazarski, C. A., Wu, Q., Bergin, I. L., . . . Zheng, P. (2017). A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 in mice. ELIFE, 6. doi:10.7554/eLife.32497

Jayappa, K. D., Portell, C. A., Gordon, V. L., Capaldo, B. J., Bekiranov, S., Axelrod, M. J., . . . Weber, M. J. (2017). Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL (vol 14, pg 933, 2017). BLOOD ADVANCES, 1(19), 1537. doi:10.1182/bloodadvances.2017011148

Ziembik, M. A., Bender, T. P., Larner, J. M., & Brautigan, D. L. (2017). Functions of protein phosphatase-6 in NF-kappa B signaling and in lymphocytes. BIOCHEMICAL SOCIETY TRANSACTIONS, 45, 693-701. doi:10.1042/BST20160169

Jayappa, K. D., Portell, C. A., Gordon, V. L., Capaldo, B. J., Bekiranov, S., Axelrod, M. J., . . . Weber, M. J. (2017). Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL. BLOOD ADVANCES, 1(14), 933-946. doi:10.1182/bloodadvances.2016004176


Xiao, C., Calado, D. P., Galler, G., Thai, T. -H., Patterson, H. C., Wang, J., . . . Rajewsky, K. (2016). MiR-150 Controls B Cell Differentiation by Targeting the Transcription Factor c-Myb.. Cell, 165(4), 1027. doi:10.1016/j.cell.2016.04.056


Rosenfeld, S. M., Perry, H. M., Gonen, A., Prohaska, T. A., Srikakulapu, P., Grewal, S., . . . McNamara, C. A. (2015). B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis. CIRCULATION RESEARCH, 117(3), E28-E39. doi:10.1161/CIRCRESAHA.117.306044


Perry, H. M., Oldham, S. N., Fahl, S. P., Que, X., Gonen, A., Harmon, D. B., . . . McNamara, C. A. (2013). Helix-Loop-Helix Factor Inhibitor of Differentiation 3 Regulates Interleukin-5 Expression and B-1a B Cell Proliferation. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 33(12), 2771-2779. doi:10.1161/ATVBAHA.113.302571


Tewalt, E. F., Cohen, J. N., Rouhani, S. J., Guidi, C. J., Qiao, H., Fahl, S. P., . . . Engelhard, V. H. (2012). Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. BLOOD, 120(24), 4772-4782. doi:10.1182/blood-2012-04-427013

Waldron, T., De Dominici, M., Soliera, A. R., Audia, A., Iacobucci, I., Lonetti, A., . . . Calabretta, B. (2012). c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells. LEUKEMIA, 26(4), 644-653. doi:10.1038/leu.2011.264

Doran, A. C., Lipinski, M. J., Oldham, S. N., Garmey, J. C., Campbell, K. A., Skaflen, M. D., . . . McNamara, C. A. (2012). .B-Cell Aortic Homing and Atheroprotection Depend on Id3. CIRCULATION RESEARCH, 110(1), E1-U6. doi:10.1161/CIRCRESAHA.111.256438

Perry, H. M., Bender, T. P., & McNamara, C. A. (2012). B cell subsets in atherosclerosis. FRONTIERS IN IMMUNOLOGY, 3. doi:10.3389/fimmu.2012.00373


Bezman, N. A., Chakraborty, T., Bender, T., & Lanier, L. L. (2011). miR-150 regulates the development of NK and iNKT cells. JOURNAL OF EXPERIMENTAL MEDICINE, 208(13), 2717-2731. doi:10.1084/jem.20111386

Bezman, N. A., Chakraborty, T., Bender, T., & Lanier, L. L. (2011). miR-150 regulates the development of NK and iNKT cells. The Journal of Cell Biology, 195(6), i7. doi:10.1083/jcb1956oia7

Matalova, E., Buchtova, M., Tucker, A. S., Bender, T. P., Janeckova, E., Lungova, V., . . . Smarda, J. (2011). Expression and characterization of c-Myb in prenatal odontogenesis. DEVELOPMENT GROWTH & DIFFERENTIATION, 53(6), 793-803. doi:10.1111/j.1440-169X.2011.01287.x

Bender, T. P., Gonda, T. J., Frampton, J., Ness, S. A., & Ramsay, R. G. (2011). Professor Alan M Gewirtz (1949-2010) OBITUARY. ONCOGENE, 30(19), 2187. doi:10.1038/onc.2011.78

Gimferrer, I., Hu, T., Simmons, A., Wang, C., Souabni, A., Busslinger, M., . . . Alberola-Ila, J. (2011). Regulation of GATA-3 Expression during CD4 Lineage Differentiation. JOURNAL OF IMMUNOLOGY, 186(7), 3892-3898. doi:10.4049/jimmunol.1003505


Bender, T. P. (2010). A new window on c-Myb function. BLOOD, 116(8), 1190-1191. doi:10.1182/blood-2010-06-287300

Hu, T., Simmons, A., Yuan, J., Bender, T. P., & Alberola-Ila, J. (2010). The transcription factor c-Myb primes CD4(+)CD8(+) immature thymocytes for selection into the iNKT lineage. NATURE IMMUNOLOGY, 11(5), 435-U98. doi:10.1038/ni.1865

Yuan, J., Crittenden, R. B., & Bender, T. P. (2010). c-Myb Promotes the Survival of CD4(+)CD8(+) Double-Positive Thymocytes through Upregulation of Bcl-xL. JOURNAL OF IMMUNOLOGY, 184(6), 2793-2804. doi:10.4049/jimmunol.0902846

Trampont, P. C., Tosello-Trampont, A. -C., Shen, Y., Duley, A. K., Sutherland, A. E., Bender, T. P., . . . Ravichandran, K. S. (2010). CXCR4 acts as a costimulator during thymic beta-selection. NATURE IMMUNOLOGY, 11(2), 162-U86. doi:10.1038/ni.1830