Restoration of TET2 function blocks aberrant self-renewal and leukemia progression Journal Article

   


Authors: Cimmino, L.; Dolgalev, I.; Wang, Y.; Yoshimi, A.; Martin, G. H.; Wang, J.; Ng, V.; Xia, B.; Witkowski, M. T.; Mitchell-Flack, M.; Grillo, I.; Bakogianni, S.; Ndiaye-Lobry, D.; Martín, M. T.; Guillamot, M.; Banh, R. S.; Xu, M.; Figueroa, M. E.; Dickins, R. A.; Abdel-Wahab, O.; Park, C. Y.; Tsirigos, A.; Neel, B. G.; Aifantis, I.
Article Title: Restoration of TET2 function blocks aberrant self-renewal and leukemia progression
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 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. PaperClip [Formula presented] © 2017 Elsevier Inc.
Keywords: leukemia; self-renewal; hscs; tet2; parp inhibitor; vitamin c; dna demethylation; hydroxymethylcytosine; dna oxidation; reversible rnai
Journal Title: Cell
Volume: 170
Issue: 6
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2017-09-07
Start Page: 1079
End Page: 1095.e20
Language: English
DOI: 10.1016/j.cell.2017.07.032
PROVIDER: scopus
PUBMED: 28823558
PMCID: PMC5755977
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85027458667&doi=10.1016%2fj.cell.2017.07.032&partnerID=40&md5=c6410eb9a2dd2f21c748bb2d4012de16
Notes: Article -- Export Date: 4 October 2017 -- Source: Scopus
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MSK Authors
  1. Omar Ibrahim Abdel-Wahab
    573 Abdel-Wahab
  2. Akihide Yoshimi
    35 Yoshimi
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