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

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

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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 κ 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.

元の言語英語
ページ(範囲)852-864
ページ数13
ジャーナルJournal of Clinical Investigation
119
発行部数4
DOI
出版物ステータス出版済み - 4 1 2009

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Mercher, T., Raffel, G. D., Moore, S. A., Cornejo, M. G., Baudry-Bluteau, D., Cagnard, N., Jesneck, J. L., Pikman, Y., Cullen, D., Williams, I. R., Akashi, K., Shigematsu, H., Bourquin, J. P., Giovannini, M., Vainchenker, W., Levine, R. L., Lee, B. H., Bernard, O. A., & Gilliland, D. G. (2009). The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. Journal of Clinical Investigation, 119(4), 852-864. https://doi.org/10.1172/JCI35901