title: MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.
abstract: 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.
authors: Division of Hematology/Oncology, Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors: Kathrin M
authors: KM
authors: Bernt
authors: Nan
authors: N
authors: Zhu
authors: Amit U
authors: AU
authors: Sinha
authors: Sridhar
authors: S
authors: Vempati
authors: Joerg
authors: J
authors: Faber
authors: Andrei V
authors: AV
authors: Krivtsov
authors: Zhaohui
authors: Z
authors: Feng
authors: Natalie
authors: N
authors: Punt
authors: Amanda
authors: A
authors: Daigle
authors: Lars
authors: L
authors: Bullinger
authors: Roy M
authors: RM
authors: Pollock
authors: Victoria M
authors: VM
authors: Richon
authors: Andrew L
authors: AL
authors: Kung
authors: Scott A
authors: SA
authors: Armstrong
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D015321:Gene Rearrangement / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D006410:Hematopoiesis; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011499:Protein Processing, Post-Translational
chemical_list: D006657:Histones; D018398:Homeodomain Proteins; C474558:MLL-AF9 fusion protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine