The Myb locus encodes the c-Myb transcription factor, which functions as both a transcription activator and repressor. c-Myb is absolutely required for definitive hematopoiesis and has been implicated in a variety of hematopoitic tumors including leukemia and lymphoma as well as solid tumors. In collaboration with Calabretta and colleagues, we recently demonstrated that loss of a single Myb allele severely reduces colony formation in bone marrow progenitors transduced with a p210BCR/ABL producing virus and extended survival in a model of CML blast crisis. This finding has been extended to transformation of B-lineage progenitors in two models of p190BCR/ABL-dependent B-cell leukemia (Waldron et al., manuscript submitted) and in this proposal we provide preliminary evidence that c-Myb is important for the continued survival and proliferation of Abl transformed pre-B cells. Thus, understanding what c-Myb does during normal hematopoiesis and identifying the downstream mediators of c-Myb activity is crucial for understanding c-Myb function during normal hematopoiesis and how c-Myb may function in cancer. However, gaining insight into c-Myb function has been difficult due to the embryonic lethality of null Myb mutations. We have produced mice that carry a loxP targeted Myb locus for conditional deletion by Cre recombinase. We have used these mice to define critical points during B cell development where c-Myb is required. c-Myb is required for the development, proliferation and survival of pro-B cells, transition from the pro-B to pre-B cell compartment as well as maintenance of the pre-B cell compartment. In addition, we reported that c-Myb is crucial for peripheral B cell homeostasis and that c-Myb deficient B cells are hyporesponsive to BAFF, displaying both reduced expression of BAFF-R and increased nuclear distribution of PKC-(. We have used these models to identify tentative targets of c-Myb activity that may mediate downstream c-Myb functions during B cell development. The goal of this proposal is to develop the network of crucial genes that mediate c-Myb activity during different stages of B cell development.

Public Health Relevance

The Myb locus encodes the c-Myb protooncogene, which functions as a transcription regulator. c-Myb is absolutely required for normal hematopoiesis and is associated with a wide variety of human leukemias, lymphomas and other malignancies such as breast and colon cancer. Completion of the proposed work will clarify the role played by c-Myb during normal B cell development and identify direct targets of c-Myb activity that will provide insight into how c-Myb functions in normal hematopoiesis and cancer and identify potential therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM100776-04
Application #
8665994
Study Section
Special Emphasis Panel (ZRG1-IMM-G (02))
Program Officer
Marino, Pamela
Project Start
2011-09-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$288,383
Indirect Cost
$98,383
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904