FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N 6-Methyladenosine RNA Demethylase

Cancer Cell. 2017 Jan 9;31(1):127-141. doi: 10.1016/j.ccell.2016.11.017. Epub 2016 Dec 22.

Abstract

N6-Methyladenosine (m6A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m6A in cancer have been limited. Here we show that FTO, as an m6A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m6A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m6A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response.

Keywords: AML; ASB2; ATRA; FTO; RARA; RNA modification; RNA stability; cell differentiation; leukemogenesis; m6A.

Publication types

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

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / physiology*
  • Apoptosis
  • Cell Proliferation
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / pathology
  • Methylation
  • Retinoic Acid Receptor alpha / physiology
  • Suppressor of Cytokine Signaling Proteins / physiology
  • Transcriptome
  • Tretinoin / pharmacology

Substances

  • ASB2 protein, human
  • RARA protein, human
  • Retinoic Acid Receptor alpha
  • Suppressor of Cytokine Signaling Proteins
  • N(6)-methyladenosine
  • Tretinoin
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human
  • Adenosine