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Ferrata Storti Foundation
Haematologica 2021 Volume 106(12):3176-3187
Expression of the chemokine receptor CCR1 promotes the dissemination of multiple myeloma plasma cells in vivo
Mara N. Zeissig,1,2 Duncan R. Hewett,1,2 Vasilios Panagopoulos,1,2 Krzysztof M. Mrozik,1,2 L. Bik To,3 Peter I. Croucher,4,5 Andrew C.W. Zannettino1,2,6,7# and Kate Vandyke1,2#
1Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia; 2Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia; 3Department of Hematology, Royal Adelaide Hospital, Adelaide, South Australia; 4Bone Biology Division, Garvan Institute of Medical Research, Sydney, New South Wales; 5St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales; 6Central Adelaide Local Health Network, Adelaide, New South Wales and 7Center for Cancer Biology, University of South Australia, Adelaide, New South Wales, Australia.
#ACWZ and KV contributed equally as co-senior authors.
ABSTRACT
Multiple myeloma (MM) disease progression is dependent on the ability of MM plasma cells (PC) to egress from the bone marrow (BM), enter the circulation and disseminate to distal BM sites. Expression of the chemokine CXCL12 by BM stromal cells is crucial for MM PC retention within the BM. However, the mechanisms which over- come CXCL12-mediated retention to enable dissemination are poorly understood. We have previously identified that treatment with the CCR1 ligand CCL3 inhibits the response to CXCL12 in MM cell lines, suggesting that CCL3/CCR1 signaling may enable egress of MM PC from the BM. Here, we demonstrated that CCR1 expression was an independent prog- nostic indicator in newly diagnosed MM patients. Furthermore, we showed that CCR1 is a crucial driver of dissemination in vivo, with CCR1 expression in the murine MM cell line 5TGM1 being associated with an increased incidence of bone and splenic disseminated tumors in C57BL/KaLwRij mice. Furthermore, we demonstrated that CCR1 knock- out in the human myeloma cell line OPM2 resulted in a >95% reduction in circulating MM PC numbers and BM and splenic tumor dissemination following intratibial injection in NSG mice. Therapeutic targeting of CCR1 with the inhibitor CCX9588 significantly reduced OPM2 or RPMI-8226 dissemination in intratibial xenograft models. Collectively, our findings suggest a novel role for CCR1 as a critical driver of BM egress of MM PC during tumor dissemination. Furthermore, these data suggest that CCR1 may represent a potential therapeutic target for the prevention of MM tumor dissemination.
Introduction
Multiple myeloma (MM) is an incurable hematological cancer characterized by the uncontrolled proliferation of clonal plasma cells (PC) within the bone marrow (BM).1 One of the key features of MM is the presence of MM PC at multiple sites throughout the BM, highlighting that dissemination of transformed PC is a critical process during disease development.1,2 In support of this, circulating MM PC are detectable by flow cytometry in approximately 75% of newly diagnosed MM patients.3 Importantly, the presence of elevated circulating MM PC predicts faster time to progression and poorer overall survival, independent of BM tumor burden.4-12
The dissemination of MM PC is a multi-step process requiring release from the supportive niche in the BM, intravasation into nearby blood vessels and subsequent
Plasma Cell Disorders
Correspondence:
KATE VANDYKE
kate.vandyke@adelaide.edu.au
Received: March 25, 2020. Accepted: October 23, 2020. Pre-published: November 5, 2020.
https://doi.org/10.3324/haematol.2020.253526 ©2021 Ferrata Storti Foundation
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