Description:

The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents:

Iannis Aifantis, PhD
Professor and Chair, Department of Pathology
NYU School of Medicine

Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, MDS, and AML, and are associated with a DNA hypermethylation phenotype. To determine the role of TET2-deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and αKG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, enhanced TET-mediated DNA oxidation induced by vitamin C treatment synergizes with PARP inhibition to kill leukemia cells, and could provide a safe and effective combination strategy to selectively target TET-deficiency in cancer.