title: Histone Acetyltransferase Activity of MOF Is Required forMLL-AF9Leukemogenesis.
abstract: Chromatin-based mechanisms offer therapeutic targets in acute myeloid leukemia (AML) that are of great current interest. In this study, we conducted an RNAi-based screen to identify druggable chromatin regulator-based targets in leukemias marked by oncogenic rearrangements of theMLLgene. In this manner, we discovered the H4K16 histone acetyltransferase (HAT) MOF to be important for leukemia cell growth. Conditional deletion ofMofin a mouse model ofMLL-AF9-driven leukemogenesis reduced tumor burden and prolonged host survival. RNA sequencing showed an expected downregulation of genes within DNA damage repair pathways that are controlled by MOF, as correlated with a significant increase in yH2AX nuclear foci inMof-deficientMLL-AF9tumor cells. In parallel,Mofloss also impaired global H4K16 acetylation in the tumor cell genome. Rescue experiments with catalytically inactive mutants of MOF showed that its enzymatic activity was required to maintain cancer pathogenicity. In support of the role of MOF in sustaining H4K16 acetylation, a small-molecule inhibitor of the HAT component MYST blocked the growth of both murine and humanMLL-AF9leukemia cell lines. Furthermore,Mofinactivation suppressed leukemia development in anNUP98-HOXA9-driven AML model. Taken together, our results establish that the HAT activity of MOF is required to sustainMLL-AF9leukemia and may be important for multiple AML subtypes. Blocking this activity is sufficient to stimulate DNA damage, offering a rationale to pursue MOF inhibitors as a targeted approach to treatMLL-rearranged leukemias.Cancer Res; 77(7); 1753-62. ©2017 AACR.
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Daria G
authors.initials: DG
authors.lastname: Valerio
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Haiming
authors.initials: H
authors.lastname: Xu
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hoshii
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Eisold
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christopher
authors.initials: C
authors.lastname: Delaney
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Monica
authors.initials: M
authors.lastname: Cusan
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Aniruddha J
authors.initials: AJ
authors.lastname: Deshpande
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.
authors.forename: Amaia
authors.initials: A
authors.lastname: Lujambio
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.
authors.forename: YuJun George
authors.initials: YG
authors.lastname: Zheng
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York. scott_armstrong@dfci.harvard.edu.|Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage; D005260:Female; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*
chemical_list: D006657:Histones; D018398:Homeodomain Proteins; C474558:MLL-AF9 fusion protein, human; C400441:NUP98-HOXA9 fusion protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human