A MOUSE MODEL OF ACUTE MEGAKARYOBLASTIC LEUKEMIA TO REVEAL NOVEL THERAPEUTIC VULNERABILITIES

Experimental Hematology(2019)

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摘要
Non-down syndrome pediatric acute megakaryoblastic leukemia (AMKL, AML M7; FAB classification) is an aggressive disease, and classical protocols used for the treatment of AML in children with AMKL have proven unsuccessful. This is largely due to current poor understanding of the molecular mechanisms by which oncogenics fusions – which are frequently occurring in pediatric but not adult AMKL - drive leukemogenesis and sustain cellular self-renewal. We recently developed a mouse model of AKML as a tool to identify and characterize novel therapeutic targets. AMKL was generated with a penetrance of 50-70% and affected mice displayed striking splenomegaly. Our model recapitulates many features of the human disease which is characterized by an accumulation of megakaryocytic blasts in the peripheral blood and bone marrow as well as infiltration into extramedullary tissues such as the spleen and liver. Blasts also express one or more megakaryocyte markers (CD61, CD41, CD42, factor VIII), and the morphology of bone marrow and spleen cells is consistent with megakaryoblasts and megakaryocytes. In addition, increased proportions of stem and progenitor cells (c-Kit+/Sca1+), progenitors (c-Kit+/Sca1-) and immature megakaryoblasts (c-Kit+/CD41+) were detected in the spleen and bone marrow of leukemic mice. Finally, genome-wide RNA sequencing of leukemic blasts revealed a megakaryocytic signature (Itga2b, Itgb3, Gp1ba, Vwf), while gene set enrichment analysis uncovered, among other pathways, increased Notch and Wnt/s-catenin signalling with an altered metabolic gene expression profile. To conclude, by taking advantage of our mouse model, we are currently investigating signalling pathways that are altered in leukemic megakaryoblasts to ultimately uncover unique therapeutic vulnerabilities specific to pediatric non-DS AMKL.
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