Recently, Professor Ji Chunyan’s team of the Department of Hematology of Qilu Hospital of Shandong University, published an article in Leukemia, an authoritative international journal in the field of hematology and oncology on August 1, 2022, revealing the cancer-promoting effect of M6A methylated "reading protein" IGF2BP2 in T-ALL. The research results entitled "METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4" was online published in Leukemia (Chinese Academy of Sciences (CAS)District 1; IF=12.883). The work revealed the regulatory effect of M6A methylated "writing protein" METTL3 on chemotherapy resistance in acute myeloid leukemia (AML) for the first time.  This study confirmed that METTL3 can regulate homing of AML cells by regulating the M6A methylation of ITGA4 mRNA, and ultimately mediate the occurrence of chemotherapy resistance. The conclusion of this study comprehensively reveals the new mechanism of M6A methylation modification system in AML resistance, and is expected to provide a highly promising treatment strategy for targeted combination therapy of refractory / recurrent AML. Professor Ji Chunyan and researcher Sun Tao are co-corresponding authors of this article. Li Mingying, a doctoral student, and Professor Ye Jingjing from the Department of Hematology of Qilu Hospital are co-first authors. Qilu Hospital of Shandong University is the first author’s and corresponding author’s affiliation.

Drug resistance and relapse of leukemia are one of the most common causes of death in AML patients. AML cells homing and colonizing in the bone marrow microenvironment can interact with stromal cells and then effectively avoid the killing of chemotherapeutic drugs, which is an important reason for the chemotherapeutic resistance of AML cells.  In this study, multi-group analysis showed that METTL3 was significantly related to chemotherapy resistance of AML, and further experiments in vitro and in vivo confirmed that M6A methylation mediated by METTL3 can induce chemotherapy resistance of AML.  On this basis, this study found for the first time the promoting effect of METTL3 on bone marrow homing and colonization of AML cells, and suggested that METTL3 inhibitors can improve the chemotherapy resistance of AML cells and animals by reversing the bone marrow homing and colonization of drug-resistant cells.  Finally, this study confirmed that METTL3 regulates the homing and colonization of AML cells by prolonging the half-life of ITGA4 mRNA and increasing the expression of ITGA4 protein. This study for the first time revealed the function of M6A methylation in the interaction between AML cells and bone marrow microenvironment, clarified the specific mechanism of METTL3-mediated AML chemotherapy resistance, and provided strong evidence for the treatment of refractory / recurrent AML combined with METTL3 inhibitors.
Professor Ji Chunyan's team has been committed to basic and clinical research on leukemia for a long time, insisting on treating basic research as the basis and clinical research the key. At the same time, his team fully excavate the link function of interdisciplinary cooperation, and try to achieve the breakthrough and clinical transformation of accurate diagnosis and treatment of leukemia.  In recent years, Prof. Ji’s team has made many innovative achievements in the pathogenesis and drug resistance mechanism of leukemia, targeted therapy and accurate diagnosis and treatment of artificial intelligence, which have been funded by National Natural Science Foundation (including major research projects), Mount Tai Scholars Climbing Program and many provincial and ministerial programs. The team has published more than 100 articles in high-level academic journals. The main research results "Abnormal Biological Behavior of Leukemia and its Reversal Countermeasures" and "R&D, Popularization and Application of Key Technologies for Accurate Diagnosis and Treatment of Leukemia" won the first prize of the Shandong Provincial Scientific and Technological Progress Prize in 2012 and 2021 respectively.
Link：https://www.nature.com/articles/s41375-022-01696-w

By Sun Yingtao, Chen Teng