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
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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Research Article Oncology

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 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.

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

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Figure 2

OTT-MAL induces abnormal fetal and adult hematopoiesis and AMKL with low penetrance.

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OTT-MAL induces abnormal fetal and adult hematopoiesis and AMKL with low...
(A) Plating efficiency of LSK cells. Mean ± SD of the number and type of colony counted after 7 days in triplicate is shown. (B) Colonies from A were replated into fresh methylcellulose plates and were scored 7 days later. Mean ± SD of 3 independent experiments is shown. Mk, CFU-Mk; E, blast-forming unit–erythroid; GM, CFU–granulocyte-macrophage. (C) Serial replating assays of splenocytes from 18- to 24-month-old OM, Ott3lox/WT, and WT littermate animals. Mean value of the number of colonies is indicated. (D) Kaplan-Meier survival curves of secondary (IIary) and tertiary (IIIary) recipients injected with 1 × 106 splenocytes from 6127 (WT) and 6133 (OM). (E) Immunohistochemistry on BM sections from secondary recipients using vWF antibody. Cells expressing vWF show a dark brown coloration. Original magnification, ×100; ×1000 (insets). (F) Proliferation of 6133 cells in absence or presence of SCF (10 ng/ml). Of note, proliferation of 6133 cells was not dependent on TPO. (G) Wright-Giemsa staining of the 6133 cell line. Original magnification, ×1000. (H) Flow cytometrical immunophenotype of 6133 cells. Percentages of live cells are indicated.