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: Thomas Mercher, Glen D Raffel, Sandra A Moore, Melanie G Cornejo, Dominique Baudry-Bluteau, Nicolas Cagnard, Jonathan L Jesneck, Yana Pikman, Dana Cullen, Ifor R Williams, Koichi Akashi, Hirokazu Shigematsu, Jean-Pierre Bourquin, Marco Giovannini, William Vainchenker, Ross L Levine, Benjamin H Lee, Olivier A Bernard, D Gary Gilliland
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 119 Issue 4 Pg. 852-64 (Apr 2009) ISSN: 1558-8238 [Electronic] United States
• PMID: 19287095 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulin J Recombination Signal Sequence-Binding Protein
• Mpl protein, mouse
• OTT-MAL fusion protein, human
• Oncogene Proteins, Fusion
• Rbpj protein, mouse
• Receptors, Notch
• Receptors, Thrombopoietin

Topics

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