Dissecting the Mechanism of Apoptosis and Leukemic Transformation In Myelodysplasia

Abstract

AbstractAbstract 610A central question in the pathogenesis of the myelodysplastic syndromes (MDS) is the mechanism of apoptosis in early disease, and how this is overcome during disease progression to acute myeloid leukemia (AML). In humans, increased serum and bone marrow levels of TNF and/or FASL in early MDS implicate the cell-extrinsic apoptotic pathway, whereas increased expression of anti-apoptotic BCL2-related proteins (the cell-intrinsic pathway) has been linked to leukemic transformation. Here, we have employed the Vav-NUP98-HOXD13 (NHD13) transgenic mouse model to genetically dissect the molecular mechanisms underpinning apoptosis and leukemic progression in MDS. Three month old NHD13 mice recapitulate ‘low-risk’ human MDS with peripheral blood cytopenias, impaired in vitro progenitor cell growth, dysplasia of myeloid cells and megakaryocytes, and prominent apoptosis. Leukemic transformation in NHD13 mice occurs between 6 and 14 months of age. Using gene targeted mouse lines crossed with NHD13 mice, we show that neither TNF nor FasL are required for apoptosis. In contrast, enforced expression of Bcl2 rescues the early MDS phenotype including the macrocytic anemia, dysplasia of megakaryocytes, apoptosis and impaired erythroid and myeloid progenitor cell growth. Remarkably, enforced expression of Bcl2 completely prevented transformation to AML. Our results challenge many of the concepts regarding apoptosis in MDS. First, apoptosis is the predominant mechanism of peripheral cytopenias including erythroid-megakaryocyte dysplasia. Second, apoptosis is mediated by the BCL2-related cell intrinsic pathway. Third, overcoming apoptosis is unlikely to be an important mechanism of leukemic transformation. Indeed, our results extend recent evidence that apoptosis may be a ‘driver’ of leukemic transformation rather than a protective mechanism. These findings raise the therapeutic potential of BCL2 mimetic drugs for treating cytopenias and preventing leukemic transformation of MDS. Disclosures:No relevant conflicts of interest to declare.