In a murine model for myeloid leukemogenesis, the c-myb gene is a primary target of insertional. A recent focus of the laboratory has been to clarify the biological roles of c-Myb in leukemia progression and identify specific genes that are regulated by c-Myb at the transcriptional level. We have found that c-Myb transforms cells through multiple mechanisms including: 1) positive regulation of cell growth by both directly transactivating a cell proliferation gene(s) such as c-myc as well as preventing upregulation in monocytic cells of tumor suppressor(s) 2) inhibition of apoptosis by transactivating Bcl-2. The way in which c-Myb affects tumor suppressor expression is the subject of our most recent research on Myb transformation. Interesting, we have found that, in c-Myb transformed cells and in differentiating myeloid cells constitutively expressing c-Myb, the tumor suppressor p15Ink4b, a cdk inhibitor, is specifically prevented from being turned on. This is a characteristic of cells constitutively expressing c-Myb, but not those constitutively expressing B-Myb or c-Myc. In normal cells this tumor suppressor is upregulated during differentiation and associated with growth arrest of myeloid cells. We confirmed that in our leukemias in which the c-myb is activated by insertional mutagenesis the p15Ink4b gene is not methylated as it is in a great majority of human AMLs and lymphomas of human and murine origin. Our recent studies contribute to the idea that c-Myb has several roles as a transcription factor that individually can enhance leukemia cell outgrowth.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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Wolff, Linda; Bies, Juraj (2013) p15Ink4b Functions in determining hematopoietic cell fates: Implications for its role as a tumor suppressor. Blood Cells Mol Dis 50:227-31
Slape, Christopher; Hartung, Helge; Lin, Ying-Wei et al. (2007) Retroviral insertional mutagenesis identifies genes that collaborate with NUP98-HOXD13 during leukemic transformation. Cancer Res 67:5148-55
Rosu-Myles, Michael; Taylor, Barbara J; Wolff, Linda (2007) Loss of the tumor suppressor p15Ink4b enhances myeloid progenitor formation from common myeloid progenitors. Exp Hematol 35:394-406
Markus, Jan; Garin, Matthew T; Bies, Juraj et al. (2007) Methylation-independent silencing of the tumor suppressor INK4b (p15) by CBFbeta-SMMHC in acute myelogenous leukemia with inv(16). Cancer Res 67:992-1000
Wolff, Linda; Ackerman, Steven J; Nucifora, Giuseppina (2005) Meeting report: Sixth International Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukemia, Annapolis, May 1-4, 2005. Exp Hematol 33:1436-42
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