Journal of Clinical & Experimental Pathology
Open Access

Abstract

Mutations in mixed lineage leukemia protein (MLL) are the major cause of a distinctive, biphenotypic leukemia of mixed identity, which have extremely poor prognostic outcomes. Recurrent chromosomal translocation for MLL accounts for 5-10% in acute myeloid leukemia (AML) and almost 70% infant acute lymphoblastic leukemia (ALL). In addition to MLL translocation, MLL amplification and tandem duplications were also found in acute leukemia patients. MLL is a well-established positive regulator of HOX genes (e.g. HOXA9 and MEIS1) and functions through its catalytic activity for H3 K4 methylation, a chromatin mark correlated with transcription activation. Using structure based rational design, we have developed potent peptidomimetics for that inhibit MLL histone methyltransferase activity. We have demonstrated that the lead compound, MM-401, effectively inhibits H3 K4 methylation by MLL both in vitro and in vivo . We have shown that MM-401 specifically impairs cell growth and viability of human and murine leukemia cell lines that harbor MLL rearrangement. It also promotes differentiation of leukemia blasts. Mechanism studies have shown that MM-401 reduces H3 K4 methylation at MLL target genes, which leads to the down regulation of HOXA9 and MEIS1. for These results point to a promising new therapeutics for leukemia treatment.

Biography

Dr. Yali Dou received a Ph.D. (Biology, 2000) from the University of Rochester and completed postdoctoral training at The Rockefeller University (2002-2006). In 2006, Dr. Dou joined the faculty of the Department of Pathology as an Assistant Professor. Dr. Yali Dou was the recipient of the Irvington Institute for Immunological Research Fellowship, the AACR Gertrude B. Elion Cancer Research Award (2010), the Stand Up to Cancer IRG Award (2011) and the Leukemia & Lymphoma Society Scholar Award (2012). She has published more than 35 papers in reputed journals and serving as an editorial board member of Journal of Clinical & Experimental Pathology.