It is clear that the c-myb protooncogene plays a crucial role during hematopoiesis. In each hematopoietic lineage, c-myb is abundantly expressed at the immature stages of differentiation and is turned off at a relatively late time during the differentiation process. However, virtually nothing is known about what role c-myb plays during hematopoietic maturation, how that role is mediated or what the signaling pathways are that regulate c-myb expression. Mice that are homozygous null at the c-myb locus die at day fifteen during embryogenesis from a severe anemia. This finding graphically demonstrated the significance of c-myb during hematopoiesis but has precluded study of c-myb activity at the later stages of differentiation. The lack of a tractable genetic system that will allow mutation of c-myb during the later stages of hematopoietic maturation has been a major impediment to understanding the role of c-myb during hematopoiesis. During T-cell development in the thymus, c-myb is expressed in CD4+CD8+ double positive thymocytes but is expressed at essentially undetectable levels in CD4+ and CD8+ single positive cells. In the periphery, c-myb is not expressed in resting T-cells, but is expressed in proliferating T-cells in late Gi/early S-phase of the cell cycle. To begin to understand the role played by c-myb during T-cell development we have produced mice that carry a c-myb allele targeted with loxP sites for deletion by the Cre recombinase. By breeding these mice to available mouse strains that direct Cre expression either to the early stages of T-cell development in the thymus or in an inducible fashion, we will define the role played by c-myb during T-cell development and the activation of effector functions. In addition, these mice will be crucial to the field and will allow one to begin to gain insight into c-myb function during hematopoiesis as well as in other systems where c-myb function remains poorly understood. The goals of this proposal are: 1) to determine at what stage c-myb expression is essential for T-cell development and function, 2) to determine the consequences of inappropriate c-myb expression to T-cell development and function and 3) to identify c-myb functional domains required to drive T-cell development in the thymus.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085842-04
Application #
6694802
Study Section
Immunobiology Study Section (IMB)
Program Officer
Mccarthy, Susan A
Project Start
2001-01-05
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
4
Fiscal Year
2004
Total Cost
$361,806
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Bezman, Natalie A; Chakraborty, Tirtha; Bender, Timothy et al. (2011) miR-150 regulates the development of NK and iNKT cells. J Exp Med 208:2717-31
Gimferrer, Idoia; Hu, Taishan; Simmons, Amie et al. (2011) Regulation of GATA-3 expression during CD4 lineage differentiation. J Immunol 186:3892-8
Hu, Taishan; Simmons, Amie; Yuan, Joan et al. (2010) The transcription factor c-Myb primes CD4+CD8+ immature thymocytes for selection into the iNKT lineage. Nat Immunol 11:435-41
Trampont, Paul C; Tosello-Trampont, Annie-Carole; Shen, Yuelei et al. (2010) CXCR4 acts as a costimulator during thymic beta-selection. Nat Immunol 11:162-70
Bender, Timothy P (2010) A new window on c-Myb function. Blood 116:1190-1
Yuan, Joan; Crittenden, Rowena B; Bender, Timothy P (2010) c-Myb promotes the survival of CD4+CD8+ double-positive thymocytes through upregulation of Bcl-xL. J Immunol 184:2793-804
Smith, Emily; von Vietinghoff, Sibylle; Stark, Matthew A et al. (2009) T-lineage cells require the thymus but not VDJ recombination to produce IL-17A and regulate granulopoiesis in vivo. J Immunol 183:5685-93
Lidonnici, Maria Rosa; Corradini, Francesca; Waldron, Todd et al. (2008) Requirement of c-Myb for p210(BCR/ABL)-dependent transformation of hematopoietic progenitors and leukemogenesis. Blood 111:4771-9
Xiao, Changchun; Calado, Dinis Pedro; Galler, Gunther et al. (2007) MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131:146-59
Chen, J; Kremer, C S; Bender, T P (2006) The carbonic anhydrase I locus contains a c-Myb target promoter and modulates differentiation of murine erythroleukemia cells. Oncogene 25:2758-72

Showing the most recent 10 out of 13 publications