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HIF-2alpha Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Abstract

Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2alpha may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2alpha upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells in vitro We also found that HIF-2alpha strongly induced expression of the chemokine receptor CCR1 in multiple myeloma PCs. CCR1 activation potently induces multiple myeloma PC migration toward CCL3 while abrogating the multiple myeloma PC migratory response to CXCL12. In addition, increased CCR1 expression by multiple myeloma PCs conferred poor prognosis in newly diagnosed multiple myeloma patients and was associated with an increase in circulating multiple myeloma PCs in these patients. Taken together, our results suggest a role for hypoxia-mediated CCR1 upregulation in driving the egress of multiple myeloma PCs from the bone marrow. Targeting CCR1 may represent a novel strategy to prevent dissemination and overt relapse in multiple myeloma. Cancer Res; 77(20); 5452-63. (c)2017 AACR.

Type Journal
ISBN 1538-7445 (Electronic) 0008-5472 (Linking)
Authors Vandyke, K.; Zeissig, M. N.; Hewett, D. R.; Martin, S. K.; Mrozik, K. M.; Cheong, C. M.; Diamond, P.; To, L. B.; Gronthos, S.; Peet, D. J.; Croucher, P. I.; Zannettino, A. C. W.
Responsible Garvan Author Prof Peter Croucher
Publisher Name CANCER RESEARCH
Published Date 2017-10-31 00:00:00
Published Volume 77
Published Issue 20
Published Pages 5452-5463
Status Published in-print
DOI 10.1158/0008-5472.CAN-17-0115
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/28855206