title: The H3K4-Methyl Epigenome Regulates Leukemia Stem Cell Oncogenic Potential.
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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Stephen H K
authors.initials: SH
authors.lastname: Wong
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Goode
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwasaki
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wei
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Hsu-Ping
authors.initials: HP
authors.lastname: Kuo
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schneidawind
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Duque-Afonso
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: mcleary@stanford.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cleary
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D006657:Histones; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine