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Molecular Basis of p53 Functional Inactivation by the Leukemic Protein MLL-ELL

Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115,¹ Ph.D. Program in Biological Sciences in Public Health, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts 02138,² Edward A. Doisy Department of Biochemistry, St. Louis University School of Medicine, St. Louis, Missouri 63104³

Received 5 November 2002/ Returned for modification 17 December 2002/ Accepted 18 March 2003

The Eleven Lysine-rich Leukemia (ELL) gene undergoes translocation and fuses in frame to the Multiple Lineage Leukemia (MLL) gene in a substantial proportion of patients suffering from acute forms of leukemia. Molecular mechanisms of cellular transformation by the MLL-ELL fusion are not well understood. Although both MLL-ELL and wild-type ELL can reduce functional activity of p53 tumor suppressor, our data reveal that MLL-ELL is a much more efficient inhibitor of p53 than is wild-type ELL. We also demonstrate for the first time that ELL extreme C terminus [ELL(eCT)] is required for the recruitment of p53 into MLL-ELL nuclear foci and is both necessary and sufficient for the MLL-ELL inhibition of p53-mediated induction of p21 and apoptosis. Finally, our results demonstrate that MLL-ELL requires the presence of intact ELL(eCT) in order to disrupt p53 interactions with p300/CBP coactivator and thus significantly reduce p53 acetylation in vivo. Since ELL(eCT) has recently been shown to be both necessary and sufficient for MLL-ELL-mediated transformation of normal blood progenitors, our data correlate ELL(eCT) contribution to MLL-ELL transformative effects with its ability to functionally inhibit p53.

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