MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.

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.

[1]  DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. , 2011, Blood.

[2]  J. Mesirov,et al.  GenePattern 2.0 , 2006, Nature Genetics.

[3]  N. Zeleznik-Le,et al.  Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes. , 2010, Cancer research.

[4]  Xiaobo Xia,et al.  H3K79 methylation profiles define murine and human MLL-AF4 leukemias. , 2008, Cancer cell.

[5]  C. Allis,et al.  Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers , 2010, Nature Reviews Cancer.

[6]  T. Golub,et al.  Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9 , 2006, Nature.

[7]  J. Issa,et al.  DNA Methylation as a Therapeutic Target in Cancer , 2007, Clinical Cancer Research.

[8]  Dafydd G. Thomas,et al.  Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. , 2011, Blood.

[9]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[10]  H. Broxmeyer,et al.  The kit receptor and its ligand, steel factor, as regulators of hemopoiesis. , 1991, Cancer cells.

[11]  Arndt Borkhardt,et al.  Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization , 2004, Molecular and Cellular Biology.

[12]  Wolfram Goessling,et al.  The Wnt/β-Catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML , 2010, Science.

[13]  Laurence Florens,et al.  Histone Crosstalk between H2B Monoubiquitination and H3 Methylation Mediated by COMPASS , 2007, Cell.

[14]  Axel Benner,et al.  Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. , 2008, The New England journal of medicine.

[15]  Toshiki Mori,et al.  ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. , 2002, Molecular cell.

[16]  Joshua F. McMichael,et al.  DNMT3A mutations in acute myeloid leukemia. , 2010, The New England journal of medicine.

[17]  Thomas A Milne,et al.  MLL targets SET domain methyltransferase activity to Hox gene promoters. , 2002, Molecular cell.

[18]  Yi Zhang,et al.  Structure of the Catalytic Domain of Human DOT1L, a Non-SET Domain Nucleosomal Histone Methyltransferase , 2003, Cell.

[19]  C. Bach,et al.  Misguided Transcriptional Elongation Causes Mixed Lineage Leukemia , 2009, PLoS biology.

[20]  E. Lander,et al.  MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia , 2002, Nature Genetics.

[21]  K. Davies,et al.  The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. , 2007, Human molecular genetics.

[22]  H. Drexler,et al.  Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders , 2010, Nature Genetics.

[23]  R. Kuiper,et al.  Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes , 2010, Nature Genetics.

[24]  K. Helin,et al.  Histone methyltransferases in cancer. , 2010, Seminars in cell & developmental biology.

[25]  A. Shilatifard,et al.  AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. , 2010, Molecular cell.

[26]  S. Gore,et al.  DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. , 2008, Seminars in hematology.

[27]  M. Groudine,et al.  H3 K79 dimethylation marks developmental activation of the beta-globin gene but is reduced upon LCR-mediated high-level transcription. , 2008, Blood.

[28]  J. Downing,et al.  Gene Expression Profiling of Pediatric Acute Myelogenous Leukemia Materials and Methods , 2022 .

[29]  T. Fields,et al.  Early mammalian erythropoiesis requires the Dot1L methyltransferase. , 2010, Blood.

[30]  Christopher R. Vakoc,et al.  DOT1L/KMT4 Recruitment and H3K79 Methylation Are Ubiquitously Coupled with Gene Transcription in Mammalian Cells , 2008, Molecular and Cellular Biology.

[31]  De-Pei Liu,et al.  A conserved, extended chromatin opening within α-globin locus during development , 2005 .

[32]  Yi Zhang,et al.  hDOT1L Links Histone Methylation to Leukemogenesis , 2005, Cell.

[33]  Jiaying Tan,et al.  The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. , 2010, Cancer cell.

[34]  A. Shilatifard,et al.  Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). , 2010, Genes & development.

[35]  A. Chinnaiyan,et al.  A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. , 2007, Blood.

[36]  Wenzheng Zhang,et al.  Dot1a-AF9 Complex Mediates Histone H3 Lys-79 Hypermethylation and Repression of ENaCα in an Aldosterone-sensitive Manner* , 2006, Journal of Biological Chemistry.

[37]  Scott A. Armstrong,et al.  MLL translocations, histone modifications and leukaemia stem-cell development , 2007, Nature Reviews Cancer.

[38]  J. Hess,et al.  Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. , 2005, Cancer research.

[39]  Ali Shilatifard,et al.  Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis , 2010, Nature Reviews Cancer.

[40]  Mark Johnston,et al.  Linking cell cycle to histone modifications: SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation. , 2009, Molecular cell.

[41]  Richard A Young,et al.  Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. , 2008, Genes & development.

[42]  M. Cleary,et al.  Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins , 2001, Oncogene.

[43]  R. Humphries,et al.  Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells , 1999, Leukemia.

[44]  Kristian Helin,et al.  Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. , 2006, Genes & development.

[45]  De-Pei Liu,et al.  A conserved, extended chromatin opening within alpha-globin locus during development. , 2005, Experimental cell research.

[46]  M. Cleary,et al.  A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. , 2010, Cancer cell.

[47]  D. Charnock-Jones,et al.  vavCre Transgenic mice: A tool for mutagenesis in hematopoietic and endothelial lineages , 2002, Genesis.