METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification
By Hengyou Weng, Huilin Huang, Huizhe Wu, Xi Qin, B. Zhao, Lei Dong, Hailing Shi, Jennifer Skibbe, Chao Shen, Chao Hu and 19 more. Cell Stem Cell, 2017
860 citations recorded by the source corpus.
SUMMARY N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic messenger RNAs (mRNAs), plays critical roles in many bioprocesses. However, its functions in normal and malignant hematopoiesis remain elusive. Here we report METTL14, a key component of the m6A methyltransferase complex, is highly expressed in normal hematopoietic stem/progenitor cells (HSPCs) and acute myeloid leukemia (AML) cells carrying t(11q23), t(15;17), or t(8;21), and is down-regulated during myeloid differentiation. Silencing of METTL14 promotes terminal myeloid differentiation of normal HSPCs and AML cells, and inhibits AML cell survival/proliferation. METTL14 is required for development/maintenance of AML and self-renewal of leukemia stem/initiation cells (LSCs/LICs). Mechanistically, METTL14 exerts its oncogenic role by regulating its mRNA targets (e.g., MYB and MYC) through m6A modification, while itself is negatively regulated by SPI1. Collectively, our results reveal the SPI1⊣METTL14-MYB/MYC signaling axis in myelopoiesis and leukemogenesis, and highlight the critical roles of METTL14 and m6A modification in normal and malignant hematopoiesis.
Subfields: Cancer Research, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/7d53279a84e709ec295990c28d4160a56de7171f
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Citations in the corpus
- RNA modifications modulate gene expression during development (2018, neutral): “Interestingly, the stabilization of certain m 6 A methylated transcripts in AML cells may be mediated by the IGF2BP1-3 family of m 6 A reader proteins rather than the YTHDF1-3 family ( 12, 57 ).”
- m6A RNA methylation: from mechanisms to therapeutic potential (2021, positive): “Three independent reports implicate METTL3 or METTL14 as important regulators of AML, suggesting that targeting m 6 A may hold therapeutic potential in this setting (Barbieri et al , 2017; Vu et al , 2017; Weng et al , 2018a).”
- Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “reported very recently that METTL14 is highly expressed in normal hematopoietic stem/progenitor cells and in various subtypes of acute myeloid leukemia (AML), and plays a critical oncogenic role in the development and maintenance of AML by blocking myeloid differentiation and promoting self-renewal ”
- The role of m6A RNA methylation in cancer metabolism (2022, background): “Inhibition METTL14 expression results in a significant decreasing of the half-life of MYB and MYC transcripts, thus inhibiting tumor progression [88].”
- Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection (2020, background): “METTL14 silencing leads to inhibition of AML cell growth and survival [65].”
- RNA N6-methyladenosine modification in cancers: current status and perspectives (2018, background): “We found that METTL14 is highly expressed in normal HSPCs and is downregulated during myeloid differentiation, and depletion of METTL14 expression further promotes terminal myeloid differentiation of normal HSPCs.75 METTL14 is also aberrantly overexpressed in human AMLs, especially those carrying t(”
- m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer (2018, neutral): “Although our results suggest that decreased m 6 A methylation promotes tumorigenesis in the endometrium, other cancers are associated with high METTL3 expression and increased m 6 A methylation and could involve different mechanisms 24,32–34 .”