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J. Biol. Chem., Vol. 280, Issue 34, 30254-30262, August 26, 2005

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Enhanced Proliferative Potential of Hematopoietic Cells Expressing Degradation-resistant c-Myb Mutants^*

Francesca Corradini¶, Vincenzo Cesi¶, Viviana Bartella¶, Elisabetta Pani¶||, Rita Bussolari¶, Olivia Candini, and Bruno Calabretta**

From the Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, Pennsylvania 19107 and the Department of Medical Sciences, University of Modena and Reggio Emilia, 41100 Modena, Italy

The c-myb gene encodes a transcription factor required for proliferation, differentiation, and survival of hematopoietic cells. Expression of c-Myb is often increased in hematological malignancies, but the underlying mechanisms are poorly understood. We show here that c-Myb has a longer half-life (at least 2-fold) in BCR/ABL-expressing than in normal hematopoietic cells. Such enhanced stability was dependent on a phosphatidylinositol 3-kinase (PI-3K)/Akt/GSKIII pathway(s) as indicated by the suppression of c-Myb expression upon treatment with PI-3K inhibitors or co-expression with dominant negative Akt or constitutively active GSKIII. Moreover, inhibition of GSKIII by LiCl enhanced c-Myb expression in parental 32Dcl3 cells. Compared with wild type c-Myb, three mutants ((358–452), (389–418), and L389A/L396A c-Myb) of the leucine zipper domain had increased stability. However, only expression of (358–452) was not affected by inhibition of the PI-3K/Akt pathway and was not enhanced by a proteasome inhibitor, suggesting that leucine zipper-dependent and -independent mechanisms are involved in the regulation of c-Myb stability. Indeed, (389–418) carrying four lysine-to-alanine substitutions ((389–418) K387A/K428A/K442A/K445A) was as stable as (358–452) c-Myb. Compared with full-length c-Myb, constitutive expression of (358–452) and (389–418) c-Myb in Lin-Sca-1⁺ mouse marrow cells increased cytokine-dependent primary and secondary colony formation. In K562 cells, expression of (358–452), (389–418), and L389A/L396A c-Myb led to enhanced proliferation after STI571 treatment. Thus, enhanced stability of c-Myb by activation of PI-3K-dependent pathway(s) might contribute to the higher proliferative potential of BCR/ABL-expressing and, perhaps, other leukemic cells.

Received for publication, April 29, 2005 , and in revised form, May 26, 2005.

^* This work was supported in part by NCI, National Institutes of Health, Grant CA95111 (to B. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains an additional figure.

^¶ These authors contributed equally to this work.

^|| Supported in part by a fellowship of the A. Serra Association for Cancer Research.

^** To whom correspondence should be addressed: Kimmel Cancer Center, Thomas Jefferson University, BLSB, Rm. 630, 233 S. 10th St., Philadelphia, PA 19107. Tel.: 215-503-4522; Fax: 215-923-0249; E-mail: bruno.calabretta{at}mail.tju.edu.

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