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Publication

METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification.

Cell stem cell | 2018

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 that 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 downregulated 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 and 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 the protein 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.

Pubmed ID: 29290617 RIS Download

Research resources used in this publication

CD11b Monoclonal Antibody (M1/70), PE, eBioscience (RRID:AB_465546) (antibody)

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Associated grants

Agency: NHLBI NIH HHS, United States
Id: R01 HL131444
Agency: NHGRI NIH HHS, United States
Id: RM1 HG008935
Agency: NCI NIH HHS, United States
Id: R01 CA236399
Agency: NCI NIH HHS, United States
Id: R50 CA211404
Agency: NCI NIH HHS, United States
Id: R01 CA182528
Agency: Howard Hughes Medical Institute, United States
Agency: NCI NIH HHS, United States
Id: R01 CA214965
Agency: NIDDK NIH HHS, United States
Id: R01 DK107615
Agency: NCI NIH HHS, United States
Id: R01 CA243386
Agency: NCI NIH HHS, United States
Id: R01 CA178454
Agency: NCI NIH HHS, United States
Id: R01 CA211614

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JASPAR (tool)

RRID:SCR_003030

Open source database of curated, non-redundant set of profiles derived from published collections of experimentally defined transcription factor binding sites for multicellular eukaryotes. Consists of open data access, non-redundancy and quality. JASPAR CORE is smaller set that is non-redundant and curated. Collection of transcription factor DNA-binding preferences, modeled as matrices. These can be converted into Position Weight Matrices (PWMs or PSSMs), used for scanning genomic sequences. Web interface for browsing, searching and subset selection, online sequence analysis utility and suite of programming tools for genome-wide and comparative genomic analysis of regulatory regions. New functions include clustering of matrix models by similarity, generation of random matrices by sampling from selected sets of existing models and a language-independent Web Service applications programming interface for matrix retrieval.

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