TY - JOUR
T1 - Pro-inflammatory macrophages promote multiple myeloma resistance to bortezomib therapy
AU - Beyar-Katz, Ofrat
AU - Magidey, Ksenia
AU - Reiner-Benaim, Anat
AU - Barak, Noga
AU - Avivi, Irit
AU - Cohen, Yael
AU - Timaner, Michael
AU - Avraham, Shimrit
AU - Hayun, Michal
AU - Lavi, Noa
AU - Bersudsky, Marina
AU - Voronov, Elena
AU - Apte, Ron N.
AU - Shaked, Yuval
N1 - Funding Information:
This work was supported primarily by an ERC grant given to Y. Shaked (771112). This project was also supported by Israel Cancer Association Grant (to R.N. Apte and E. Voronov), Israel Cancer Research Fund (to R.N. Apte and E. Voronov), and Binational (Israel–USA) Science Foundation Grant 2011263 (to R.N. Apte and E. Voronov). R.N. Apte is an incumbent of the Irving Isaac Sklar Chair in Endocrinology and Cancer. O. Beyar-Katz was supported by a Gassner Fund for Medical Research. Bone marrow aspirates from MM patients were obtained from MIDGAM-Israel National Biobank for Research. We thank Ayelet Itzhaki, head of Institutional Biobank at Tel Aviv Sourasky Medical Center, for assisting with sample collection.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074378593&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-19-0487
DO - 10.1158/1541-7786.MCR-19-0487
M3 - Article
C2 - 31409628
AN - SCOPUS:85074378593
VL - 17
SP - 2331
EP - 2340
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 11
ER -