MLL-rearranged Leukemia is Dependent on Aberrant H3K79 Methylation by DOT1L

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2011 Jul 12

PMID 21741597

Citations 496

Authors

Kathrin M Bernt

Nan Zhu

Amit U Sinha

Sridhar Vempati

Joerg Faber

Andrei V Krivtsov

Zhaohui Feng

Natalie Punt

Amanda Daigle

Lars Bullinger

Roy M Pollock

Victoria M Richon

Andrew L Kung

Scott A Armstrong

Affiliations

Soon will be listed here.

Abstract

The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.

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