title: Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles.
abstract: t(8;21) is one of the most frequent chromosomal abnormalities observed in acute myeloid leukemia (AML). However, expression of AML1-ETO is not sufficient to induce transformation in vivo. Consistent with this observation, patients with this translocation harbor additional genetic abnormalities, suggesting a requirement for cooperating mutations. To better define the genetic landscape in AML and distinguish driver from passenger mutations, we compared the mutational profiles of AML1-ETO-driven mouse models of leukemia with the mutational profiles of human AML patients. We identified TET2 and PTPN11 mutations in both mouse and human AML and then demonstrated the ability of Tet2 loss and PTPN11 D61Y to initiate leukemogenesis in concert with expression of AML1-ETO in vivo. This integrative genetic profiling approach allowed us to accurately predict cooperating events in t(8;21)(+) AML in a robust and unbiased manner, while also revealing functional convergence in mouse and human AML.
authors.affiliation: Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Weill Cornell Graduate School of Medical Sciences, New York, NY 10065.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Hatlen
authors.affiliation: New York Genome Center, New York, NY 10013.
authors.forename: Kanika
authors.initials: K
authors.lastname: Arora
authors.affiliation: New York Genome Center, New York, NY 10013.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vacic
authors.affiliation: New York Genome Center, New York, NY 10013.
authors.forename: Ewa A
authors.initials: EA
authors.lastname: Grabowska
authors.affiliation: New York Genome Center, New York, NY 10013.
authors.forename: Willey
authors.initials: W
authors.lastname: Liao
authors.affiliation: New York Genome Center, New York, NY 10013.
authors.forename: Bridget
authors.initials: B
authors.lastname: Riley-Gillis
authors.affiliation: New York Genome Center, New York, NY 10013.
authors.forename: Dayna M
authors.initials: DM
authors.lastname: Oschwald
authors.affiliation: Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Joergens
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Shih
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Franck
authors.initials: F
authors.lastname: Rapaport
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario M5G 2M9, Canada Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Shengqing
authors.initials: S
authors.lastname: Gu
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Francesca
authors.initials: F
authors.lastname: Voza
authors.affiliation: Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Takashi
authors.initials: T
authors.lastname: Asai
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario M5G 2M9, Canada Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.affiliation: Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Center for Cellular Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kharas
authors.affiliation: Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Mithat
authors.initials: M
authors.lastname: Gonen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065 snimer@med.miami.edu leviner@mskcc.org.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136 Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136 snimer@med.miami.edu leviner@mskcc.org.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D015973:Gene Expression Regulation, Leukemic; D055786:Gene Knockout Techniques; D023281:Genomics / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D014178:Translocation, Genetic
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11