[PDF][PDF] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression

L Cimmino, I Dolgalev, Y Wang, A Yoshimi, GH Martin… - Cell, 2017 - cell.com
Cell, 2017cell.com
Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis,
myelodysplastic syndrome (MDS), and acute myeloid leukemia (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 (HSPC) self-renewal in vitro and in vivo. Treatment …
Summary
Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (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 (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and α-KG-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, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer.
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