The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia

Cancer Cell. 2022 Dec 12;40(12):1566-1582.e10. doi: 10.1016/j.ccell.2022.10.004. Epub 2022 Oct 27.


N6-Methyladenosine (m6A) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an m6A binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an m6A-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and m6A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.

Keywords: GPT2; IGF2BP2; MYC; SLC1A5; acute myeloid leukemia; glutamine metabolism; leukemia stem cells; m(6)A modification; mitochondria oxygen consumption; targeted therapy.

Publication types

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

MeSH terms

  • Amino Acid Transport System ASC / genetics
  • Amino Acid Transport System ASC / metabolism
  • Glutamine* / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Minor Histocompatibility Antigens
  • Prognosis
  • RNA Stability
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism


  • Glutamine
  • SLC1A5 protein, human
  • Minor Histocompatibility Antigens
  • Amino Acid Transport System ASC
  • IGF2BP2 protein, human
  • RNA-Binding Proteins