Exosomes mediate intercellular transference of non-autonomous tolerance to proteasome inhibitors in mixed-lineage leukemia.

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 mixed-lineage leukemia (MLL), which consistent with the finding that patients could regain sensitivity to PIs after a drug holiday. Exosomes released from PI-treated cells could transmit PI resistance to sensitive cells via facilitating cell cycle arrest and stemness pathway in MLL cells. Furthermore, TieDIE algorithm integration analysis of transcriptome and proteome datasets identified candidate exosomal proteins, providing potential therapeutic targets for treating refractory MLL. Overall design: Examination of differential expressive genes in RS4;11 cells under Bortezomib therapeutic stress, or treated with naïve RS4;11-derived exosomes (RS4;11-Nexo) or proteasome inhibitor-treated cells released exosomes (RS4;11-Rexo).