Details

Autor(en) / Beteiligte

• Ge, Maolin
• Qiao, Zhi
• Kong, Yan
• Lu, Hui
• Liu, Han

Titel

Exosomes mediate intercellular transfer of non–autonomous tolerance to proteasome inhibitors in mixed‐lineage leukemia

Ist Teil von

• Cancer science, 2020-04, Vol.111 (4), p.1279-1290

Ort / Verlag

England: John Wiley & Sons, Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Proteasome inhibitors significantly improve cancer outcomes, but their use is eventually followed by proteasome inhibitor resistance and relapse. Current understanding of proteasome inhibitor resistance is limited to cell‐autonomous mechanisms; whether non–autonomous mechanisms can be implicated in the development of proteasome inhibitor resistance is unclear. Here, we show that proteasome inhibitor tolerance can be transmitted non–autonomously through exosome‐mediated intercellular interactions. We revealed that reversible proteasome inhibitor resistance can be transmitted from cells under therapy stress to naïve sensitive cells through exosome‐mediated cell cycle arrest and enhanced stemness in mixed‐lineage leukemia cells. Integrated multi‐omics analysis using the Tied Diffusion through Interacting Events algorithm identified several candidate exosomal proteins that may serve as predictors for proteasome inhibitor resistance and potential therapeutic targets for treating refractory mixed‐lineage leukemia. Furthermore, inhibiting the secretion of exosomes is a promising strategy for reversing proteasome inhibitor resistance in vivo, which provides a novel proof of principle for the treatment of other refractory or relapsed cancers. Using the integrated multi‐omics analysis, our study demonstrates that exosomes derived from MLL cells under therapy stress transmit proteasome inhibitor (PI) tolerance to recipient cells through cell cycle arrest and enhanced stemness. Exosomes can act not only as a mediator of development of PI tolerance but also as a therapeutic target to overcome PI resistance, thereby enhancing clinical benefits of PI therapy in MLL.