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

Abstract

N-methyladenosine (mA), 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 mA 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 mA 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 mA modification in normal and malignant hematopoiesis.

Identification of three m6A‐related mRNAs signature and risk score for the prognostication of hepatocellular carcinoma

“…METTL14 can positively regulate the primary microRNA 126 process in an m6A‐dependent manner to inhibit the metastatic potential of HCC . METTL14, as an important m6A methyltransferase, has been identified as playing an important role in many physiological functions and is also related to the occurrence and development of a variety of cancers . In addition, METTL14 has become a new target for treatment in EBV‐associated tumors …”

N6-Methyladenosine Role in Acute Myeloid Leukaemia

“…Consistent with METTL3 and METTL14 playing an oncogenic role in AML, overexpression of both genes in AML cell lines and primary blasts increased proliferation, while their downregulation impaired proliferation and resulted in a strong induction of apoptosis [51,52,53]. The oncogenic function of m 6 A was also demonstrated in primary cells derived from an AML mouse model carrying the oncogenic MLL-AF9 fusion gene and the FLT3 internal tandem duplication (FLT3-ITD), two chromosomal translocations that characterized aggressive AML subtypes and that drive AML in mouse.…”

A dynamic reversible RNA N6‐methyladenosine modification: current status and perspectives

“…A recent study demonstrate METTL14 is highly expressed in normal hematopoietic stem/progenitor cells (HSPCs) and various acute myeloid leukemia (AML) cells. The critical roles of METTL14 in normal myelopoiesis and AML pathogenesis was confirmed as featured by blocking myeloid differentiation and promoting self‐renewal of normal HSPCs and leukemia stem/initiation cells (LSCs/LICs), and uncovering a previously unrecognized signaling axis involving SPI1‐METTL14‐MYB/MYC in normal and malignant myelopoiesis (Weng et al, ). In patients with AML cells, elevated levels of FTO may reduce the m 6 A levels of tumor suppressor genes ASB2 and RARA mRNA and regulate their expressions Finally the leukemia proto‐oncogene‐mediated leukemia cell transformation was promoted.…”