title: Dominant-negative Ikaros cooperates with BCR-ABL1 to induce human acute myeloid leukemia in xenografts.
abstract: Historically, our understanding of mechanisms underlying human leukemogenesis are inferred from genetically engineered mouse models. Relatively, few models that use primary human cells recapitulate the full leukemic transformation as assayed in xenografts and myeloid transformation is infrequent. We report a humanized experimental leukemia model where xenografts develop aggressive acute myeloid leukemia (AML) with disseminated myeloid sarcomas within 4 weeks following transplantation of cord blood transduced with vectors expressing BCR-ABL1 and a dominant-negative isoform of IKAROS, Ik6. Ik6 induced transcriptional programs in BCR-ABL1-transduced progenitors that contained repressed B-cell progenitor programs, along with strong stemness, proliferation and granulocyte-monocytic progenitor (GMP) signatures-a novel combination not induced in control groups. Thus, wild-type IKAROS restrains stemness properties and has tumor suppressor activity in BCR-ABL1-initiated leukemia. Although IKAROS mutations/deletions are common in lymphoid transformation, they are found also at low frequency in AML that progress from a prior myeloproliferative neoplasm (MPN) state. Our experimental system provides an excellent model to gain insight into these rare cases of AML transformation and the properties conferred by IKAROS loss of function as a secondary mutation. More generally, our data points to the importance of deregulated stemness/lineage commitment programs in human myeloid leukemogenesis.
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada [3] Division of Hematology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: A P A
authors.initials: AP
authors.lastname: Theocharides
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: S M
authors.initials: SM
authors.lastname: Dobson
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Laurenti
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Notta
authors.affiliation: Pathway and Network Analyses for OICR Cancer Stem Cell Research, Terrence Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Ontario, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Voisin
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: P-Y
authors.initials: PY
authors.lastname: Cheng
authors.affiliation: Developmental & Stem Cell Biology Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
authors.forename: J S
authors.initials: JS
authors.lastname: Yuan
authors.affiliation: Developmental & Stem Cell Biology Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: Guidos
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada [3] Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Ontario, Canada [4] Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada [5] Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: C G
authors.identifier: 0000000218711850
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Laboratory Hematology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Torlakovic
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D005799:Genes, Dominant; D064593:Heterografts; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics / Q000473:pathology
chemical_list: C581634:BCR-ABL1 fusion protein, human; C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl