The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model
Thomas Mercher, … , Olivier A. Bernard, D. Gary Gilliland
Thomas Mercher, … , Olivier A. Bernard, D. Gary Gilliland
Published March 16, 2009
Citation Information: J Clin Invest. 2009;119(4):852-864. https://doi.org/10.1172/JCI35901.
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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 7

OTT-MAL+MPLW515L–induced AMKL shows characteristics of human AMKL.

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OTT-MAL+MPLW515L–induced AMKL shows characteristics of human AMKL. (...
(A) White blood counts in secondary recipients. Mean ± SD of 5 animals is shown. (B) Platelet counts in secondary recipients. Mean ± SD of 5 animals is shown. (C) Kaplan-Meier survival curves of secondary and tertiary transplant recipients. (D) Flow cytometry analysis of splenocytes at 40 days after transplantation. Percentages of live cells are indicated. (E) vWF immunohistochemistry on spleen sections from secondary recipients. Original magnification, ×1000. (F) Ploidy analysis was performed by flow cytometry using propidium iodide (PI). Histograms show a representative analysis gated on 10,000 CD41+ cells. (G) Histopathologic analysis of BM reticulin fibrosis in secondary recipients. Original magnification, ×100. (H) Proposed model of leukemogenesis by OTT-MAL. In WT cells, repressor complexes are recruited to RBPJ in the absence of Notch stimulation. Following Notch stimulation, intracellular Notch (ICN) translocates to the nucleus, displaces corepressors, and binds RBPJ to allow recruitment of the coactivator MAML and expression of target genes. We propose that OTT-MAL aberrantly activates RBPJ-mediated transcription in the absence of Notch stimulation and leads to increased differentiation of hematopoietic progenitors to the Mk lineage. Full AMKL transformation requires additional cooperating events (i.e., activation of MPL signaling). Minus sign indicates inhibition of transcription; plus signs indicate activation of transcription.