Vitamin C-induzierte DNA-Demethylierung als Präventivtherapie für Leukämie

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Mutations in genes that either encode or affect the function of epigenetic regulators are frequent early events in aging-related clonal hematopoiesis and were found to precede leukemic transformation in longitudinal patient studies. Correspondingly, a large proportion of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients show genome-wide alterations in chromatin methylation. Recent work, including the host lab’s, has identified gains in cytosine methylation at enhancer elements in response to isocitrate dehydrogenase (IDH) and ten-eleven translocation dioxygenase (TET) mutations to directly affect myeloid differentiation in murine models. The host lab showed that vitamin C, which activates a set of enzymes that catalyze genome demethylation, can resolve enhancer hypermethylation and thereby re-initiate expression of key myeloid genes in vitro. These findings suggest that TET and IDH mutations actively contribute to the block of differentiation that is a hallmark of AML and that this can be readily reversed by a known, non-toxic molecule. In this proposal, I suggest to explore the efficacy of vitamin C both individually and in combination with other demethylating therapies in pre-clinical in vivo settings. Further, considering that TET and IDH mutations can be detected in individuals prior to disease outbreak using routine diagnostic techniques, I propose to explore the potential of high dose vitamin C supplementation to restore cytosine methylation homeostasis in affected cells with the ultimate goal to delay or prevent the transformation towards myeloid malignancy.