Targeting the RNA m 6 A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia

Cell Stem Cell. 2019 Jul 3;25(1):137-148.e6. doi: 10.1016/j.stem.2019.03.021. Epub 2019 Apr 25.

Abstract

Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function, with YTHDF2 deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.

Keywords: TNFR2; YTHDF2; acute myeloid leukemia; hematopoiesis; hematopoietic stem cell; leukemic stem cells; m(6)A modification; mRNA decay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Self Renewal
  • Hematopoiesis
  • Hematopoietic Stem Cells
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplastic Stem Cells / physiology*
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • THP-1 Cells

Substances

  • RNA, Small Interfering
  • RNA-Binding Proteins
  • YTHDF2 protein, human
  • YTHDF2 protein, mouse