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PMID: 18977325 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

H3K79 methylation profiles define murine and human MLL-AF4 leukemias.

Cancer cell ·Vol. 14 ·No. 5 ·2008-11-04 ·Pages 355-68

Krivtsov AV, Feng Z, Lemieux ME, Faber J, Vempati S, Sinha AU, Xia X, Jesneck J, Bracken AP, Silverman LB, Kutok JL, Kung AL, Armstrong SA

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.

MeSH Terms
Animals Biomarkers, Tumor/genetics,metabolism Cell Differentiation Cells, Cultured Chromatin Immunoprecipitation Female Flow Cytometry Gene Expression Profiling Gene Expression Regulation, Leukemic Gene Rearrangement Histone Methyltransferases Histone-Lysine N-Methyltransferase Histones/chemistry,genetics,metabolism Homeodomain Proteins/metabolism Humans Immunophenotyping Integrases/metabolism Leukemia, Myeloid, Acute/genetics,pathology Lysine/chemistry,genetics,metabolism Male Methylation Methyltransferases/antagonists & inhibitors,physiology Mice Mice, Transgenic Myeloid-Lymphoid Leukemia Protein/physiology Oligonucleotide Array Sequence Analysis Oncogene Proteins, Fusion/physiology Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics,pathology Principal Component Analysis Protein Methyltransferases/genetics,metabolism RNA, Small Interfering/pharmacology Transcription, Genetic
Chemicals
Biomarkers, Tumor Histones Homeodomain Proteins MLL-AF4 fusion protein, human Oncogene Proteins, Fusion RNA, Small Interfering Myeloid-Lymphoid Leukemia Protein HoxA protein DOT1L protein, human Dot1l protein, mouse Histone Methyltransferases Methyltransferases Protein Methyltransferases Histone-Lysine N-Methyltransferase Cre recombinase Integrases Lysine
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Krivtsov Andrei V
Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Feng Zhaohui
Lemieux Madeleine E
Faber Joerg
Vempati Sridhar
Sinha Amit U
Xia Xiaobo
Jesneck Jonathan
Bracken Adrian P
Silverman Lewis B
Kutok Jeffery L
Kung Andrew L
Armstrong Scott A
References (39)
39 references, click to expand
  1. Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4 : 11) abnormality.
    Oncogene. 2001 Feb 15;20(7):874-8 PMID: 11314021
  2. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy.
    Blood. 2006 Jul 15;108(2):669-77 PMID: 16551973
  3. Self-excising retroviral vectors encoding the Cre recombinase overcome Cre-mediated cellular toxicity.
    Mol Cell. 2001 Jul;8(1):233-43 PMID: 11511376
  4. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins.
    Oncogene. 2001 Sep 10;20(40):5695-707 PMID: 11607819
  5. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.
    Nat Genet. 2002 Jan;30(1):41-7 PMID: 11731795
  6. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.
    Cancer Cell. 2002 Mar;1(2):133-43 PMID: 12086872
  7. MLL targets SET domain methyltransferase activity to Hox gene promoters.
    Mol Cell. 2002 Nov;10(5):1107-17 PMID: 12453418
  8. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation.
    Mol Cell. 2002 Nov;10(5):1119-28 PMID: 12453419
  9. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification.
    Cancer Cell. 2003 Feb;3(2):173-83 PMID: 12620411
  10. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling.
    Blood. 2003 Oct 15;102(8):2951-9 PMID: 12730115
  11. Model-based analysis of tiling-arrays for ChIP-chip.
    Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12457-62 PMID: 16895995
  12. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9.
    Nature. 2006 Aug 17;442(7104):818-22 PMID: 16862118
  13. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling.
    Hum Mol Genet. 2007 Jan 1;16(1):92-106 PMID: 17135274
  14. A chromatin landmark and transcription initiation at most promoters in human cells.
    Cell. 2007 Jul 13;130(1):77-88 PMID: 17632057
  15. Protein arginine-methyltransferase-dependent oncogenesis.
    Nat Cell Biol. 2007 Oct;9(10):1208-15 PMID: 17891136
  16. MLL translocations, histone modifications and leukaemia stem-cell development.
    Nat Rev Cancer. 2007 Nov;7(11):823-33 PMID: 17957188
  17. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification.
    Blood. 2007 Dec 15;110(13):4445-54 PMID: 17855633
  18. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells.
    Mol Cell Biol. 2008 Apr;28(8):2825-39 PMID: 18285465
  19. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors.
    Cell Stem Cell. 2007 Sep 13;1(3):324-37 PMID: 18371366
  20. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia.
    Cancer Cell. 2008 Jun;13(6):483-95 PMID: 18538732
  21. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization.
    Mol Cell Biol. 2004 Jan;24(2):617-28 PMID: 14701735
  22. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote.
    Genes Dev. 2004 Jun 1;18(11):1263-71 PMID: 15175259
  23. Development of murine B cell subpopulations.
    Semin Immunol. 1990 May;2(3):197-206 PMID: 1717054
  24. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome.
    Blood. 1993 May 1;81(9):2386-93 PMID: 8481519
  25. Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20.
    Genes Dev. 1993 Nov;7(11):2071-84 PMID: 8224839
  26. Inducible gene targeting in mice.
    Science. 1995 Sep 8;269(5229):1427-9 PMID: 7660125
  27. Altered Hox expression and segmental identity in Mll-mutant mice.
    Nature. 1995 Nov 30;378(6556):505-8 PMID: 7477409
  28. Defects in yolk sac hematopoiesis in Mll-null embryos.
    Blood. 1997 Sep 1;90(5):1799-806 PMID: 9292512
  29. An atlas of chromosomes in hematological malignancies. Example: 11q23 and MLL partners.
    Leukemia. 2001 Jun;15(6):987-9 PMID: 11417488
  30. Biological and therapeutic aspects of infant leukemia.
    Blood. 2000 Jul 1;96(1):24-33 PMID: 10891426
  31. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease.
    EMBO J. 2005 Jan 26;24(2):368-81 PMID: 15635450
  32. hDOT1L links histone methylation to leukemogenesis.
    Cell. 2005 Apr 22;121(2):167-78 PMID: 15851025
  33. Global and Hox-specific roles for the MLL1 methyltransferase.
    Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8603-8 PMID: 15941828
  34. The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin.
    Oncogene. 2005 Aug 18;24(35):5525-32 PMID: 15856011
  35. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  36. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions.
    Genes Dev. 2006 May 1;20(9):1123-36 PMID: 16618801
  37. A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology.
    Oncogene. 2006 May 25;25(22):3093-103 PMID: 16607274
  38. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression.
    Annu Rev Biochem. 2006;75:243-69 PMID: 16756492
  39. Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner.
    J Biol Chem. 2006 Jun 30;281(26):18059-68 PMID: 16636056
Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2008.10.001
Published
2008-11-04
Pages
355-68
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2591932
Subset
IM
Grants
NCI NIH HHS · U01 CA105423 · United States
NCI NIH HHS · K08 CA092551 · United States
NCI NIH HHS · 5U01CA105423 · United States
NCI NIH HHS · K08 CA092551-05 · United States
NCI NIH HHS · P01 CA068484-130015 · United States
NCI NIH HHS · U01 CA105423-05 · United States
NCI NIH HHS · P01 CA068484 · United States
NCI NIH HHS · 5P01CA0684841 · United States
NCI NIH HHS · K08CA92551 · United States
Databases
GEO
GSE12363
Corrections
CommentIn
PMID: 18977321
External Links
PubMed source DOI: 10.1016/j.ccr.2008.10.001 PMC Full Text View journal details
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