The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model
Copyright policy )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.
- UNIVERSITAET ZUERICH Switzerland
- University of Paris France
- University of Zurich Switzerland
- Harvard University United States
- Emory University United States
Oncogene Proteins, Fusion, Receptors, Notch, Transcription, Genetic, 610 Medicine & health, Mice, Transgenic, 2700 General Medicine, Hematopoiesis, Mice, Inbred C57BL, Disease Models, Animal, Mice, 10036 Medical Clinic, Leukemia, Megakaryoblastic, Acute, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Mutation, Animals, Humans, Oncogene Fusion, Receptors, Thrombopoietin, Signal Transduction
Oncogene Proteins, Fusion, Receptors, Notch, Transcription, Genetic, 610 Medicine & health, Mice, Transgenic, 2700 General Medicine, Hematopoiesis, Mice, Inbred C57BL, Disease Models, Animal, Mice, 10036 Medical Clinic, Leukemia, Megakaryoblastic, Acute, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Mutation, Animals, Humans, Oncogene Fusion, Receptors, Thrombopoietin, Signal Transduction
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).86 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!