METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4

Abstract

Chemoresistant leukemia relapse is one of the most common causes of death for acute myeloid leukemia (AML) patients and the homing/engraftment in bone marrow (BM) are crucial steps for AML cells to acquire chemoresistance by interacting with stromal cell components. No crosstalk between m6A modification and homing/engraftment has been reported. Here, we performed comprehensive high-throughput analyses, including RNA sequencing of CR (complete remission) and relapsed AML patients, and reverse-phase protein arrays of chemoresistant cells to identify METTL3 as a key player regulating AML chemoresistance. Then, METTL3-mediated m6A modification was proved to induce the chemoresistance in vitro and in vivo. Furthermore, AML homing/engraftment was discovered being enhanced by upregulated-METTL3 in chemoresistant cells. And the homing/engraftment and drug-resistance associated phenotypes of chemoresistant cells could be reversed by a METTL3 inhibitor. Mechanistically, METTL3 extended the half-life of ITGA4 mRNA by m6A methylation, and then, increased expression of ITGA4 protein to enhance homing/engraftment of AML cells. The results provide insights into the function of m6A modification on the interaction between AML cells and BM niches and clarify the relationship between METTL3 and AML homing/engraftment, suggesting a therapeutic strategy for the treatment of refractory/relapsed AML with METTL3 inhibitors.

HDAC1/3-dependent moderate liquid–liquid phase separation of YY1 promotes METTL3 expression and AML cell proliferation

“…Recent studies have confirmed that METTL3 is abnormally overexpressed in AML and is closely related to the occurrence and development of AML [6]. Previous studies by our group found that METTL3 also plays an important role in the chemoresistance of AML [7]. A METTL3 inhibitor has shown promising therapeutic effects in AML animal models [8].…”

Targeting RNA modifications with pharmacological agents: New frontiers in cancer therapy

“…METTL3 mediates resistance to other chemotherapeutic drugs, including platinum-etoposide in Small Cell Lung Cancer (SCLC), doxorubicin, 5-fluorouracil (5-FU), and oxaliplatin in CRC, Idarubicin in AML, and docetaxel in breast cancer. 114,[118][119][120][121][122] Downregulation of METTL3 also associates with resistance to daunorubicin and cytarabine in AML. 114 The m6A erasers FTO and ALKBH5 also mediate chemoresistance in cancer.…”

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

“…METTL3-mediated m6A modification induces the chemo-resistance in acute myeloid leukemia (AML) cells by increasing the stability of integrin subunit alpha 4 (ITGA4) mRNA [ 130 ].…”