title: The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.
abstract: Acute megakaryoblastic leukemia (AMKL) is a form of acute myeloid leukemia (AML) associated with a poor prognosis. The genetics and pathophysiology of AMKL are not well understood. We generated a knockin mouse model of the one twenty-two-megakaryocytic acute leukemia (OTT-MAL) fusion oncogene that results from the t(1;22)(p13;q13) translocation specifically associated with a subtype of pediatric AMKL. We report here that OTT-MAL expression deregulated transcriptional activity of the canonical Notch signaling pathway transcription factor recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and caused abnormal fetal megakaryopoiesis. Furthermore, cooperation between OTT-MAL and an activating mutation of the thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL) efficiently induced a short-latency AMKL that recapitulated all the features of human AMKL, including megakaryoblast hyperproliferation and maturation block, thrombocytopenia, organomegaly, and extensive fibrosis. Our results establish that concomitant activation of RBPJ (Notch signaling) and MPL (cytokine signaling) transforms cells of the megakaryocytic lineage and suggest that specific targeting of these pathways could be of therapeutic value for human AMKL.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
authors.forename: Glen D
authors.initials: GD
authors.lastname: Raffel
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Moore
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Cornejo
authors.forename: Dominique
authors.initials: D
authors.lastname: Baudry-Bluteau
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Jesneck
authors.forename: Yana
authors.initials: Y
authors.lastname: Pikman
authors.forename: Dana
authors.initials: D
authors.lastname: Cullen
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shigematsu
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bourquin
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006410:Hematopoiesis; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D007947:Leukemia, Megakaryoblastic, Acute / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051880:Receptors, Notch / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C481270:Mpl protein, mouse; C532421:OTT-MAL fusion protein, human; D015514:Oncogene Proteins, Fusion; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D053628:Receptors, Thrombopoietin