title: AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes.
abstract: Homeotic (HOX) genes are dysregulated in multiple malignancies, including several AML subtypes. We demonstrate that H3K79 dimethylation (H3K79me2) is converted to monomethylation (H3K79me1) at HOX loci as hematopoietic cells mature, thus coinciding with a decrease in HOX gene expression. We show that H3K79 methyltransferase activity as well as H3K79me1-to-H3K79me2 conversion is regulated by the DOT1L cofactor AF10. AF10 inactivation reverses leukemia-associated epigenetic profiles, precludes abnormal HOXA gene expression, and impairs the transforming ability of MLL-AF9, MLL-AF6, and NUP98-NSD1 fusions-mechanistically distinct HOX-activating oncogenes. Furthermore, NUP98-NSD1-transformed cells are sensitive to small-molecule inhibition of DOT1L. Our findings demonstrate that pharmacological inhibition of the DOT1L/AF10 complex may provide therapeutic benefits in an array of malignancies with abnormal HOXA gene expression.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA; Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Aniruddha J
authors.initials: AJ
authors.lastname: Deshpande
authors.affiliation: Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anagha
authors.initials: A
authors.lastname: Deshpande
authors.affiliation: Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Amit U
authors.initials: AU
authors.lastname: Sinha
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Liying
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Cihan
authors.affiliation: Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fazio
authors.affiliation: Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Koche
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Liuda
authors.initials: L
authors.lastname: Dzhekieva
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Ibáñez
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Dias
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Banka
authors.affiliation: Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Krivtsov
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Minkui
authors.initials: M
authors.lastname: Luo
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Pediatrics, University of Colorado Anshutz Medical Campus, Aurora, CO 80045 USA.
authors.forename: Kathrin M
authors.initials: KM
authors.lastname: Bernt
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA; Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: armstros@mskcc.org.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D008745:Methylation; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C581325:EPZ004777; D006657:Histones; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D014157:Transcription Factors; C093350:nuclear pore complex protein 98; D008780:Methyltransferases; D000241:Adenosine