Recent work has identified epigenomic features of distal regulatory elements to be dynamic and defining indicators of cellular specification and transformation. Of particular relevance is our nascent discovery of differentially methylated cytosines in regulatory DNA elements implicated in the control of myeloid differentiation in a murine model of mutant IDH1 leukemia. Strikingly, we have also found that vitamin C, a cofactor for TET, can reverse the methylation gains characteristic of the IDH1-mutant leukemic blasts in this engineered mouse model and initiate their expression of myeloid markers. These data suggest a new/additional role of TET/IDH mutations in driving an epigenetic-mediated silencing of regulatory elements required to activate myeloid differentiation. They also show that this mechanism can be readily reversed by exposing the affected cells to a known, nontoxic molecule (vitamin C). These findings raise the exciting possibility that this type of epigenetic change may constitute a more generalized mechanism contributing to the blocked differentiation phenotype of human AML blasts and one that may be targeted by strategies that have significantly reduced side effects.
1. An introduction to epigenetic dysfunction in cancer.
2. An understanding of the epigenetic features associated with gain of function IDH mutations in leukemia
3. An understanding of the role of vitamin C in the maintenance of DNA methylation homeostasis
Research And Development
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