title: H3K79 methylation profiles define murine and human MLL-AF4 leukemias.
abstract: We created a mouse model wherein conditional expression of an Mll-AF4 fusion oncogene induces B precursor acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Gene expression profile analysis of the ALL cells demonstrated significant overlap with human MLL-rearranged ALL. ChIP-chip analysis demonstrated histone H3 lysine 79 (H3K79) methylation profiles that correlated with Mll-AF4-associated gene expression profiles in murine ALLs and in human MLL-rearranged leukemias. Human MLL-rearranged ALLs could be distinguished from other ALLs by their H3K79 profiles, and suppression of the H3K79 methyltransferase DOT1L inhibited expression of critical MLL-AF4 target genes. We thus demonstrate that ectopic H3K79 methylation is a distinguishing feature of murine and human MLL-AF4 ALLs and is important for maintenance of MLL-AF4-driven gene expression.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Krivtsov
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Feng
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Lemieux
authors.forename: Joerg
authors.initials: J
authors.lastname: Faber
authors.forename: Sridhar
authors.initials: S
authors.lastname: Vempati
authors.forename: Amit U
authors.initials: AU
authors.lastname: Sinha
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Xia
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jesneck
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bracken
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D019426:Integrases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008239:Lysine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D025341:Principal Component Analysis; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D018398:Homeodomain Proteins; C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein; C473477:DOT1L protein, human; C481527:Dot1l protein, mouse; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C045073:Cre recombinase; D019426:Integrases; D008239:Lysine