Drug-tolerant cell-derived exosomes regulate proteasome inhibitor resistance pathways in MLL leukemias

ABSTRACT: The interplay between cancer cells and microenvironment can influence treatment response and plays a key role in the emergence of drug resistance. Rapidly acquired resistance prevents proteasome inhibitors (PIs) therapies from achieving stable and complete responses. Investigating the underlying mechanisms and developing effective strategies against PI resistance are highly desired in the clinic. Here we uncovered that PI resistance was reversible in MLL leukemia, which consistent with the finding that patients could regain sensitivity to PIs after a drug holiday. Exosomes derived from drug-tolerant cells could transmit PI resistance to sensitive cells via facilitating cell cycle arrest and stemness pathway in MLL leukemia cells. Furthermore, TieDIE algorithm integration analysis of transcriptome and proteome datasets identified candidate exosomal proteins, providing potential therapeutic targets for treating refractory MLL leukemia. Therefore, exosomal regulatory proteins may serve as a predictor and a potential therapeutic target for PI resistance, and inhibiting the secretion of exosomes is a promising strategy for restoring PI resistance in vivo, which provides a paradigm and may also be applied for the treatment of other cancers resulting from chemotherapy relapse.

OTHER RELATED OMICS DATASETS IN: GSE134879

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Culture

DISEASE(S): Acute Leukemia

SUBMITTER: Zhi Qiao  

LAB HEAD: Han Liu

PROVIDER: PXD014711 | Pride | 2020-05-27

REPOSITORIES: Pride