MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 2011 Jul 12;20(1):66-78
Date
07/12/2011Pubmed ID
21741597Pubmed Central ID
PMC3329803DOI
10.1016/j.ccr.2011.06.010Scopus ID
2-s2.0-79960044951 (requires institutional sign-in at Scopus site) 717 CitationsAbstract
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.
Author List
Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, Feng Z, Punt N, Daigle A, Bullinger L, Pollock RM, Richon VM, Kung AL, Armstrong SAAuthor
Nan Zhu PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Cell Cycle
Cell Differentiation
Cell Transformation, Neoplastic
Gene Rearrangement
Genetic Loci
Hematopoiesis
Histone-Lysine N-Methyltransferase
Histones
Homeodomain Proteins
Humans
Lysine
Methylation
Methyltransferases
Mice
Myeloid Ecotropic Viral Integration Site 1 Protein
Myeloid Progenitor Cells
Myeloid-Lymphoid Leukemia Protein
Neoplasm Proteins
Oncogene Proteins, Fusion
Protein Processing, Post-Translational