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The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.

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.

Pubmed ID: 19287095


  • Mercher T
  • Raffel GD
  • Moore SA
  • Cornejo MG
  • Baudry-Bluteau D
  • Cagnard N
  • Jesneck JL
  • Pikman Y
  • Cullen D
  • Williams IR
  • Akashi K
  • Shigematsu H
  • Bourquin JP
  • Giovannini M
  • Vainchenker W
  • Levine RL
  • Lee BH
  • Bernard OA
  • Gilliland DG


The Journal of clinical investigation

Publication Data

April 2, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA66996
  • Agency: NIDDK NIH HHS, Id: DK50654
  • Agency: NCI NIH HHS, Id: K08 CA111399
  • Agency: NCI NIH HHS, Id: P01 CA066996
  • Agency: NCI NIH HHS, Id: U01 CA105423

Mesh Terms

  • Animals
  • Disease Models, Animal
  • Hematopoiesis
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Leukemia, Megakaryoblastic, Acute
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Oncogene Fusion
  • Oncogene Proteins, Fusion
  • Receptors, Notch
  • Receptors, Thrombopoietin
  • Signal Transduction
  • Transcription, Genetic