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MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L

Authors :
Joerg Faber
Nan Zhu
Sridhar Vempati
Andrei V. Krivtsov
Lars Bullinger
Kathrin M. Bernt
Amit U. Sinha
Andrew L. Kung
Roy M. Pollock
Zhaohui Feng
Amanda Daigle
Scott A. Armstrong
Natalie Punt
Victoria M. Richon
Source :
Cancer Cell. 20:66-78
Publication Year :
2011
Publisher :
Elsevier BV, 2011.

Abstract

SummaryThe 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.

Details

ISSN :
15356108
Volume :
20
Database :
OpenAIRE
Journal :
Cancer Cell
Accession number :
edsair.doi.dedup.....02e37edfcaed6a1ace85f83760bd4cf4
Full Text :
https://doi.org/10.1016/j.ccr.2011.06.010