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J. Biol. Chem., Vol. 278, Issue 13, 11480-11488, March 28, 2003

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c-Myc Is Essential but Not Sufficient for c-Myb-mediated Block of Granulocytic Differentiation^*

Atul Kumar^§¶, Clement M. Lee, and E. Premkumar Reddy^**

From the  Fels Institute for Cancer Research and Molecular Biology and the ^§ M.D./Ph.D. Program, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and the ^¶ Department of Medicine, Montefiore Medical Center, Bronx, New York 10467

The c-myb proto-oncogene plays a central role in hematopoiesis and encodes a major translational product of 75 kDa. c-Myb is highly expressed in immature hematopoietic cells, and its expression is down-regulated during terminal differentiation. Deregulated expression of c-Myb has been shown to block terminal differentiation of hematopoietic cells. Here we have studied the mechanism of action and the nature of target genes through which c-Myb mediates the block in differentiation of 32Dcl3 murine myeloid cells. We show that the ectopic overexpression of c-Myb in 32Dcl3 cells results in the overexpression of c-Myc. However, enforced expression of c-Myc in 32Dcl3 cells did not alter the normal pattern of differentiation. In addition, expression of dominant-negative mutants of c-Myc relieved c-Myb-mediated block in differentiation. These results led us to conclude that c-myc is a target gene of c-Myb and activation of the c-myc gene is a necessary event in Myb-mediated transformation. However, c-Myc expression alone is inadequate to elicit the phenotypic effects seen with Myb-mediated block in differentiation of myeloid cells, suggesting that activation of additional transcriptional targets by c-Myb plays a critical role in this process.

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