Abstract
The genetic programs that maintain leukemia stem cell (LSC) self-renewal and oncogenic potential have been well defined; however, the comprehensive epigenetic landscape that sustains LSC cellular identity and functionality is less well established. We report that LSCs in MLL-associated leukemia reside in an epigenetic state of relative genome-wide high-level H3K4me3 and low-level H3K79me2. LSC differentiation is associated with reversal of these broad epigenetic profiles, with concomitant downregulation of crucial MLL target genes and the LSC maintenance transcriptional program that is driven by the loss of H3K4me3, but not H3K79me2. The H3K4-specific demethylase KDM5B negatively regulates leukemogenesis in murine and human MLL-rearranged AML cells, demonstrating a crucial role for the H3K4 global methylome in determining LSC fate.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cells, Cultured
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Epigenesis, Genetic*
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic
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HEK293 Cells
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism
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Histones / metabolism*
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Humans
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Interleukin Receptor Common gamma Subunit / deficiency
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Interleukin Receptor Common gamma Subunit / genetics
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism
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Leukemia / genetics
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Leukemia / metabolism*
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Leukemia / pathology
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Lysine / metabolism
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Methylation
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism
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Neoplastic Stem Cells / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Oligonucleotide Array Sequence Analysis
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RNA Interference
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Transplantation, Heterologous
Substances
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Histones
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Il2rg protein, mouse
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Interleukin Receptor Common gamma Subunit
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KMT2A protein, human
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Nuclear Proteins
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Repressor Proteins
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Myeloid-Lymphoid Leukemia Protein
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Jumonji Domain-Containing Histone Demethylases
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KDM5B protein, human
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Histone-Lysine N-Methyltransferase
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Lysine