An extensive network of TET2-targeting MicroRNAs regulates malignant hematopoiesis

Cell Rep. 2013 Oct 31;5(2):471-81. doi: 10.1016/j.celrep.2013.08.050. Epub 2013 Oct 10.

Abstract

The Ten-Eleven-Translocation 2 (TET2) gene, which oxidates 5-methylcytosine in DNA to 5-hydroxylmethylcytosine (5hmC), is a key tumor suppressor frequently mutated in hematopoietic malignancies. However, the molecular regulation of TET2 expression is poorly understood. We show that TET2 is under extensive microRNA (miRNA) regulation, and such TET2 targeting is an important pathogenic mechanism in hematopoietic malignancies. Using a high-throughput 3' UTR activity screen, we identify >30 miRNAs that inhibit TET2 expression and cellular 5hmC. Forced expression of TET2-targeting miRNAs in vivo disrupts normal hematopoiesis, leading to hematopoietic expansion and/or myeloid differentiation bias, whereas coexpression of TET2 corrects these phenotypes. Importantly, several TET2-targeting miRNAs, including miR-125b, miR-29b, miR-29c, miR-101, and miR-7, are preferentially overexpressed in TET2-wild-type acute myeloid leukemia. Our results demonstrate the extensive roles of miRNAs in functionally regulating TET2 and cellular 5hmC and reveal miRNAs with previously unrecognized oncogenic potential. Our work suggests that TET2-targeting miRNAs might be exploited in cancer diagnosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3' Untranslated Regions
  • 5-Methylcytosine / analogs & derivatives
  • Animals
  • Cytosine / analogs & derivatives
  • Cytosine / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Hematologic Neoplasms / genetics
  • Hematologic Neoplasms / metabolism
  • Hematologic Neoplasms / pathology
  • Hematopoiesis
  • Humans
  • Mice
  • MicroRNAs / metabolism*
  • Phenotype
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*

Substances

  • 3' Untranslated Regions
  • DNA-Binding Proteins
  • MicroRNAs
  • Proto-Oncogene Proteins
  • TET2 protein, human
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine