Abstract IA22: Targeting histone modifying enzymes in leukemia

Abstract

Abstract Leukemias harboring rearrangements of the MLL gene carry a poor prognosis. Recently, it has become increasingly clear that MLL-fusion proteins induce widespread epigenetic deregulation that may mediate much of their transforming activity. The histone methyltransferase DOT1L, which methylates histone 3 on lysine 79 (H3K79), has received particular attention. Several MLL-fusion proteins physically interact with DOT1L. Genome-wide H3K79 methylation profiles in MLL-rearranged leukemias are abnormal, and can serve to distinguish MLL-rearranged from other types of leukemias. Mechanistic studies have demonstrated that MLL-fusion proteins subvert a normal gene regulatory mechanism through aberrant hyperconversion of H3K79 methylation to higher methylated states at critical oncogenic targets including the HoxA cluster genes and Meis1. Remarkably, genetic inactivation or small molecule inhibition of DOT1L and thus H3K79 methylation affects expression of MLL-target loci and is detrimental to the leukemogenic activity of MLL-rearranged cells, thus demonstrating that transformation in these leukemias is driven by a DOT1L dependent, aberrant epigenetic program. Clinical trials of small molecule DOT1L inhibitors are in phase 1 clinical trials. Recent studies on the roles for DOT1L and H3K79 methylation in MLL-rearranged leukemias will be discussed. Citation Format: Scott A. Armstrong. Targeting histone modifying enzymes in leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA22.