The Mechanism Of PRMT6 In Maintaining Acute Myeloid Leukemia Stem Cells

Acute myeloid leukemia(AML)is a highly lethal hematological disease.Leukemia stem cells(LSCs)are the origin of the occurrence,development,drug resistance and recurrence of AML diseases.Therefore,a in-depth exploration of the specific molecular mechanism of AML development and stemness maintenance has become the key question of this field.Protein arginine methyltransferase(PRMT)family members catalyze the arginine methylation of protein substrates in a broad spectrum,which involved in signal transduction,cell metabolism,epigenetic regulation and other cellular biological processes.Moreover,recent studies have indicated that many members of PRMT family played crucial roles in hematologic malignancies.The protein arginine methyltransferase 6(PRMT6)catalyzes the asymmetric dimethylation of non-histone protein arginine and H3R2me2 a modification of histone H3.Recent studies have confirmed that PRMT6 played a key role in the development of tumors such as gastric cancer and lung cancer.However,the role of PRMT6 in AML is still unknown.This study found that the epigenetic molecule PRMT6 played an important role in AML development and LSCs maintenance.Firstly,the bioinformatic analysis suggested that PRMT6 was highly expressed in AML.More importantly,a series of in vitro and in vivo experiments confirmed that the deletion of PRMT6 damaged the LSCs stemness and delayed the AML development.In addition,the gain-of-function strategy and specific inhibitor experiments confirmed that the function of PRMT6 depended on its methyltransferase activity,while competitive transplantation experiments and flow cytometry analysis revealed that PRMT6 was not required for normal hematopoiesis and the long-term function of hematopoietic stem cells,suggesting PRMT6 may be a potential clinical therapeutic target.Mechanistically,RNA-seq and Ch IP-seq revealed that PRMT6 catalyzed asymmetric dimethylation of histone H3R2(H3R2me2a)in MFSD2 A promoter region and suppressed lipid transporter MFSD2 A mRNA expression.The inhibition of MFSD2 A expression impaired its ability to transport docosahexaenoic acid(DHA).Loss of PRMT6 upregulated MFSD2A expression that increased docosahexaenoic acid(DHA)level and impaired LSC maintenance.Collectively,this study firstly clarified the mechanism of PRMT6 in AML development,revealed the critical role of the PRMT6-MFSD2A-DHA signaling axis in maintaining AML stemness,and provided a therapeutic strategy for targeting AML LSCs.