HMGB1 ubiquitination inhibition and extracellular secretion, mediated by m6A modified-exosomal lncRNA MALAT1, creates a communication between NK92-MI cells and tumor cells to aggravate acute lymphoblastic leukemia

BACKGROUND: MALAT1 has been validated to favor the progression of acute lymphoblastic leukemia (ALL), but its detailed mechanism remains obscure. This study explored the functional roles of ALL cells-derived exosomal MALAT1 in chemoresistance and malignant growth of ALL cells, as well as its underlying mechanisms. METHODS: The expression of target molecules was evaluated by qRT-PCR, Western blotting, immunofluorescence, and immunohistochemical staining. CCK-8, EdU staining and flow cytometry were conducted to determine cell proliferation and apoptosis. RIP, RNA-pull down, Co-IP, and MeRIP were used to investigate molecular mechanisms. ALL cells were injected into nude mice to evaluate in vivo tumor formation. RESULTS: A modification raised MALAT1 stability and expression, and consequently facilitated ALL cell growth and apoptosis inhibition. Furthermore, MALAT1 was packaged into ALL cells-derived exosomes by hnRNPA2B1, and then transferred to NK92-MI cells. Exosomal MALAT1 suppressed tripartite motif-containing 27 (TRIM27)-mediated ubiquitination of High-mobility group box 1 (HMGB1) in NK92-MI cells, thereby leading to adriamycin resistance and malignant development of ALL cells. CONCLUSION: A modification, and subsequently restrained HMGB1 ubiquitination and degradation in NK92-MI cells, which resulted in adriamycin resistance and malignant growth of ALL cells. Therefore, inhibition of METTL14/MALAT1/HMGB1 axis might be a therapeutic strategy for ALL patients. HIGHLIGHTS: (1)METTL14 and MALAT1 were positively correlated in ALL samples.(2)METTL14 increased MALAT1 stability and expression in an IGF2BP1-mediated m6A manner.(3)ALL cells transferring exosomal MALAT1 suppressed TRIM27-mediated HMGB1 ubiquitination in NK92-MI cells.(4)HMGB1 silencing in NK92-MI cells enhanced adriamycin sensitivity of ALL cells.(5)MALAT1/HMGB1 axis inhibition delayed in vivo ALL growth via NK cell activation.