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Article Publish Status: FREE
Abstract Title:

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression.

Abstract Source:

Cell. 2017 Sep 7 ;170(6):1079-1095.e20. Epub 2017 Aug 17. PMID: 28823558

Abstract Author(s):

Luisa Cimmino, Igor Dolgalev, Yubao Wang, Akihide Yoshimi, Gaëlle H Martin, Jingjing Wang, Victor Ng, Bo Xia, Matthew T Witkowski, Marisa Mitchell-Flack, Isabella Grillo, Sofia Bakogianni, Delphine Ndiaye-Lobry, Miguel Torres Martín, Maria Guillamot, Robert S Banh, Mingjiang Xu, Maria E Figueroa, Ross A Dickins, Omar Abdel-Wahab, Christopher Y Park, Aristotelis Tsirigos, Benjamin G Neel, Iannis Aifantis

Article Affiliation:

Luisa Cimmino

Abstract:

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 Fe2andα-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.PAPERCLIP.

Study Type : In Vitro Study

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Sayer Ji
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