Proinflammatory macrophages promote multiple myeloma resistance to bortezomib therapy

Ofrat Beyar-Katz, Ksenia Magidey, Anat Reiner-Benaim, Noga Barak, Irit Avivi, Yael Cohen, Michael Timaner, Shimrit Avraham, Michal Hayun, Noa Lavi, Marina Bersudsky, Elena Voronov, Ron N. Apte, Yuval Shaked*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Multiple myeloma (MM) is a plasma cell neoplasia commonly treated with proteasome inhibitors such as bortezomib. Although bortezomib has demonstrated enhanced survival benefit, some patients relapse and subsequently develop resistance to such therapy. Here, we investigate the mechanisms underlying relapse and refractory MM following bortezomib treatment. We show that bortezomibexposed proinflammatory macrophages promote an enrichment of MM-tumor-initiating cells (MM-TIC) both in vitro and in vivo. These effects are regulated in part by IL1b, as blocking the IL1b axis by a pharmacologic or genetic approach abolishes bortezomib-induced MM-TIC enrichment. In MM patients treated with bortezomib, high proinflammatory macrophages in the bone marrow negatively correlate with survival rates (HR, 1.722; 95% CI, 1.138- 2.608). Furthermore, a positive correlation between proinflammatory macrophages and TICs in the bone marrow was also found. Overall, our results uncover a protumorigenic cross-talk involving proinflammatory macrophages and MM cells in response to bortezomib therapy, a process that enriches the MM-TIC population.

Original languageEnglish
Pages (from-to)2331-2340
Number of pages10
JournalMolecular Cancer Research
Issue number11
StatePublished - 2019
Externally publishedYes


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