Deletion of Mettl3 in mesenchymal stem cells promotes acute myeloid leukemia resistance to chemotherapy

Abstract

Acute myeloid leukemia (AML) cell survival and chemoresistance are influenced by the existence of bone marrow mesenchymal stem cells (BMMSCs); however, the pathways by which BMMSCs contribute to these processes remain unclear. We earlier revealed that methyltransferase-like 3 (METTL3) expression is significantly reduced in AML BMMSCs and that METTL3 mediates BMMSC adipogenesis to promote chemoresistance in human AML cell lines in vitro. In this investigation, we evaluated the METTL3 function in vivo. Mice exhibiting a conditional removal of Mettl3 in BMMSCs were developed by mating Prrx1-CreERT2;Mettl3fl/+ mice with Mettl3fl/fl mice using the CRISPR-Cas9 system. The Mettl3 deletion increased bone marrow adiposity, enhanced disease progression in the transplantation-induced MLL-AF9 AML mouse model, and chemoresistance to cytarabine. The removal of Mettl3 in BMMSCs resulted in a significant increase in BMMSC adipogenesis. This effect was attributed to the downregulation of AKT1 expression, an AKT serine/threonine kinase 1, in an m6A-dependent manner. The development of chemoresistance in AML is linked to the promoted adipogenesis of BMMSCs. We conclude that METTL3 expression in BMMSCs has a critical function in limiting AML progression and chemoresistance, providing a basis for the progression of therapeutic approaches for AML.

A new perspective on hematological malignancies: m6A modification in immune microenvironment

“…This is supported by the findings in the mouse model of Liao et al. ( 105 ). METTL3 also prolongs the half-life of ITGA4 mRNA through m6A methylation, leading to increased ITGA4 protein expression and enhanced homing/implantation of AML cells.…”

“…AKT expression was considerably lower in cells overexpressing METTL3, which triggers the PI3K/AKT pathway, promotes MSC adipogenesis, and mediates AML chemoresistance (104). This is supported by the findings in the mouse model of Liao et al (105). METTL3 also prolongs the half-life of ITGA4 mRNA through m6A methylation, leading to increased ITGA4 protein expression and enhanced homing/implantation of AML cells.…”