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Expression of the chemokine receptor CCR1 promotes the dissemination of multiple myeloma plasma cells in vivo

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dc.contributor.authorZeissig, M.N.
dc.contributor.authorHewett, D.R.
dc.contributor.authorPanagopoulos, V.
dc.contributor.authorMrozik, K.M.
dc.contributor.authorTo, L.B.
dc.contributor.authorCroucher, P.I.
dc.contributor.authorZannettino, A.C.W.
dc.contributor.authorVandyke, K.
dc.date.issued2020
dc.description.abstractMultiple 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 overcome 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 prognostic 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 knockout 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.
dc.description.statementofresponsibilityMara N. Zeissig, Duncan R. Hewett, Vasilios Panagopoulos, Krzysztof M. Mrozik, L. Bik To, Peter I. Croucher, Andrew C.W. Zannettino, and Kate Vandyke
dc.identifier.citationHaematologica, 2020; 106(12):3176-3187
dc.identifier.doi10.3324/haematol.2020.253526
dc.identifier.issn0390-6078
dc.identifier.issn1592-8721
dc.identifier.orcidZeissig, M.N. [0000-0003-3264-6546]
dc.identifier.orcidPanagopoulos, V. [0000-0002-6879-1262]
dc.identifier.orcidMrozik, K.M. [0000-0002-4890-8208]
dc.identifier.orcidZannettino, A.C.W. [0000-0002-6646-6167]
dc.identifier.orcidVandyke, K. [0000-0002-1033-849X]
dc.identifier.urihttps://hdl.handle.net/2440/133933
dc.language.isoen
dc.publisherFerrata Storti Foundation
dc.rights©2021 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
dc.source.urihttps://doi.org/10.3324/haematol.2020.253526
dc.subjectplasma cells
dc.subjectCXCL12-mediated retention
dc.subjectBM stromal cells
dc.subject.meshPlasma Cells
dc.subject.meshCell Line, Tumor
dc.subject.meshAnimals
dc.subject.meshMice, Inbred C57BL
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshMultiple Myeloma
dc.subject.meshReceptors, CCR1
dc.titleExpression of the chemokine receptor CCR1 promotes the dissemination of multiple myeloma plasma cells in vivo
dc.typeJournal article
pubs.publication-statusPublished

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