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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Apoptosis
- Cell Cycle
- Cell Differentiation
- Cell Transformation, Neoplastic / metabolism
- Cell Transformation, Neoplastic / pathology
- Gene Rearrangement / genetics*
- Genetic Loci / genetics
- Hematopoiesis
- Histone-Lysine N-Methyltransferase
- Histones / metabolism*
- Homeodomain Proteins / metabolism
- Humans
- Lysine / metabolism*
- Methylation
- Methyltransferases / metabolism*
- Mice
- Myeloid Ecotropic Viral Integration Site 1 Protein
- Myeloid Progenitor Cells / metabolism
- Myeloid Progenitor Cells / pathology
- Myeloid-Lymphoid Leukemia Protein / metabolism*
- Neoplasm Proteins / metabolism
- Oncogene Proteins, Fusion / metabolism
- Protein Processing, Post-Translational
Substances
- Histones
- Homeodomain Proteins
- MLL-AF9 fusion protein, human
- Myeloid Ecotropic Viral Integration Site 1 Protein
- Neoplasm Proteins
- Oncogene Proteins, Fusion
- homeobox protein HOXA9
- Myeloid-Lymphoid Leukemia Protein
- DOT1L protein, human
- Methyltransferases
- Histone-Lysine N-Methyltransferase
- Lysine
Associated data
- GEO/GSE25911
- GEO/GSE29130