HIF-2α 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-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells We also found that HIF-2α 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. .

Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch

“…CNI are commonly utilized to prevent allograft rejection in solid organ transplant recipients. [37][38][39] However, the overall immunosuppressive effects of CNI results in decreased antibody production and hypogammoglobulinemia. This can lead to greater morbidity and mortality associated with common infectious agents, such as influenza viruses [64][65][66].…”

“…In addition to HIF-1α stabilization, HIF-2α has also been shown to be stabilized upon hypoxic exposure of several different cell types [37,38], but there is little data in human B cells. We performed a western blot analysis of HIF-2α protein stabilization in the RAMOS human B cells under varying O 2 conditions.…”

Hematogenous extramedullary relapse in multiple myeloma ‐ a multicenter retrospective study in 127 patients

“…Lastly, the development of new therapies that interfere with cell homing and migration, e.g. CXCR4 and CCR1 antagonists respectively may represent a novel strategy to prevent myeloma dissemination outside the medullary niche.…”

Cancer stem cells and hypoxia-inducible factors (Review)

“…6) (65). The target genes participate in the proliferation, apoptosis, metabolism and invasion, as well in the and resistance of cancer cells to therapy (66)(67)(68).…”