New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m6A methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML.

The Role of RNA Methyltransferase METTL3 in Normal and Malignant Hematopoiesis

“…discovered that METTL3 is a novel oncogene in CML and potentially a therapeutic target for TKI-resistant CML. The m6A methyltransferase complex METTL3 / METTL14 and METTL3 is upregulated in primary CML patients, and its downregulation significantly impairs the proliferation of both primary CML cells and TKI-sensitive and TKI-resistant CML cells ( 60 ). Silencing METTL3 in K562 cells and the TKI imatinib mesylate-resistant K562 cell line (K562r), they found that METTL3 affects the growth and viability of CML cells directly and indirectly.…”

“…MYC, as a transcriptional activator, is notably affected by METTL3 in CML cells, including the protein, mRNA, and premRNA levels. METTL3 knockdown strongly reduced MYC expression at multiple levels in CML, which consequently regulated the genes associated with RNA metabolism ( 60 ). Moreover, they found that the PES1 protein was potentially involved in blocking the cell cycle in G1 phase after METTL3 knockdown in CML cells ( 60 ).…”

“…METTL3 knockdown strongly reduced MYC expression at multiple levels in CML, which consequently regulated the genes associated with RNA metabolism ( 60 ). Moreover, they found that the PES1 protein was potentially involved in blocking the cell cycle in G1 phase after METTL3 knockdown in CML cells ( 60 ). They showed that METTL3 both regulates PES1 by methyltransferase activity in the nucleus and directly promotes PES1 translation in the cytoplasm independently of its catalytic activity ( 60 ).…”

The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies

“…At present, it has been reported that METTL3, an RNA m 6 A modifier, is also involved in the mechanism of CML development [ 130 ]. Specifically, Ianniello et al [ 130 ] identified that the m 6 A methyltransferase complex METTL3/METTL14 is highly expressed in CML patients and is essential to maintain the proliferation of primary CML cells and CML cell lines that are sensitive or resistant to tyrosine kinase inhibitors (TKIs) (e.g., imatinib). Notably, it has been reported that aberrant translation is thought to be one of the mechanisms that mediate BCR/ABL transformation and maintain the leukemic phenotype of CML cells [ 159 , 160 ].…”

Current Advances in N6-Methyladenosine Methylation Modification During Bladder Cancer

“…METTL3 in human tissue is highly expressed and conserved, especially in the testes. Recent studies reported that METTL3 is significantly highly expressed in chronic myeloid leukemia ( Ianniello et al, 2021 ), thymic epithelial tumors ( Iaiza et al, 2021 ), esophageal cancer ( Han et al, 2021 ), and prostate cancer ( Chen et al, 2021b ), suggesting a close relationship with malignant tumor development. Previous studies also suggested that METTL3 is significantly up-regulated in BC.…”