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J. Biol. Chem., Vol. 280, Issue 26, 24315-24321, July 1, 2005

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Multiple Mixed Lineage Leukemia (MLL) Fusion Proteins Suppress p53-mediated Response to DNA Damage^*

Dmitri Wiederschain, Hidehiko Kawai, Ali Shilatifard¶, and Zhi-Min Yuan||

From the Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115 and the ^¶Edward A. Doisy Department of Biochemistry, St. Louis University School of Medicine, St. Louis, Missouri 6314

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are often observed in acute leukemias of both myeloid and lymphocytic origin. Expression of MLL fusion proteins is known to induce malignant transformation of normal blood progenitors; however, molecular mechanisms of this process are still poorly understood. In this study we investigated the effect of several frequently detected MLL fusion proteins on p53 transcriptional activity. Our data show that MLL-AF9, MLL-AF10, MLL-ENL, and MLL-ELL substantially down-regulate p53-mediated induction of p21, MDM2, and Bax in response to DNA damage. Furthermore, we identify the reduction in p53 acetylation by p300 as a major mechanism of the inhibitory effect of MLL leukemic fusions. Our data suggest that abrogation of p53 functional activity can be a common feature of MLL fusion-mediated leukemogenesis.

Received for publication, October 28, 2004 , and in revised form, March 29, 2005.

^* This work was supported in part by National Institutes of Health Grant RO1 CA85679-02 and American Cancer Society Research Scholar Grant GMC-104886 (to Z.-M. Y.). 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.

Supported by the Ruth L. Kirschstein National Research Service Award NIEHS11627. Present address: Novartis Institutes for BioMedical Research, Cambridge, MA 02139.

^|| To whom correspondence should be addressed: Dept. of Genetics and Complex Diseases, Bldg. I, Rm. 507, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. Tel.: 617-432-0763; Fax: 617-432-0107, E-mail: zyuan{at}hsph.harvard.edu.

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