Role of C-myb in Hematopoiesis and Cancer

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DESCRIPTION (provided by applicant): It is now well established that the c-myb gene encodes for two proteins, p75-Myb and p89-Myb, and plays a critical role in the development, proliferation and oncogenesis of hematopoietic cells. Because constitutive loss of the c-myb gene leads to embryonic lethality, it has not been possible to accurately assess the role of this gene in the maintenance of adult hematopoiesis. To overcome this problem and to investigate the function of this gene in adult hematopoiesis, we used the Cre-LoxP recombination system to achieve tissue-specific deletion of c-myb. In a recently published study, we have generated two T cell-specific c-myb knockout mouse models mybF/F/LckCre and mybF/F/CD4Cre, which delete c-myb at two specific stages of T cell development. Studies with these mice have allowed us to define the role of c-myb in T cell development and function. In contrast to the function of p75-c-Myb, the role of p89c-Myb in hematopoiesis is not known. To examine the function of the p89c- myb isoform, we have generated a mouse model where exon 9A is deleted, and as a consequence, this mutant mouse is incapable of producing the p89-c-Myb. A role for c-myb in leukemogenesis was established when It was shown that retrovirus-induced mouse myeloid leukemias express a C- terminal truncated form of c-myb (termed t-myb), which exhibits enhanced transactivating and transformation activities. To determine the biological effects of myb gene truncation during mouse development and hematopoiesis, we have generated a strain of mice which express a C-terminal deletional mutant of c-Myb conditionally. In this application, we propose to use these powerful mouse genetic models to determine the roles played by p75 and p89 isoforms of c-Myb in hematopoiesis and the consequence of C-terminal truncation of c-Myb in hematopoiesis and leukemogenesis. The aims are: 1. To ascertain the molecular mechanisms by which c-Myb regulates T-cell development at the DP stage, gene array and proteomics analysis will be performed, and the functions of those altered genes and proteins will be assessed using both in vivo and in vitro conditions. 2. To determine the role of c-myb in adult hematopoiesis and myeloid development. 3. To define the role of c-myb in Hematopoietic Stem Cell (HSC) development and function. 4. To determine the roles of an alternatively spliced form of c-myb, the p89c-myb, and a genetically truncated version of c-myb, t- myb, in lineage commitment, proliferation and survival of myeloid progenitors and HSCs; and 5. To examine the role of c-myb in BCRABL-mediated transformation of myeloid cells.