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

Cell. 2017 Sep 7;170(6):1079-1095.e20. doi: 10.1016/j.cell.2017.07.032. Epub 2017 Aug 17.

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.

Keywords: DNA demethylation; DNA oxidation; HSCs; PARP inhibitor; TET2; hydroxymethylcytosine; leukemia; reversible RNAi; self-renewal; vitamin C.

MeSH terms

  • Animals
  • Ascorbic Acid / administration & dosage
  • Ascorbic Acid / pharmacology*
  • Cell Death
  • Cell Line, Tumor
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Mice
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / genetics
  • Neoplasm Transplantation
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Transcription, Genetic
  • Transplantation, Heterologous
  • Vitamins / administration & dosage
  • Vitamins / pharmacology*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TET2 protein, human
  • Tet2 protein, mouse
  • Vitamins
  • Poly (ADP-Ribose) Polymerase-1
  • Ascorbic Acid