In:
Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 130-130
Abstract:
Abstract 130 Multiple myeloma (MM) bone marrow (BM) provides a homing microenvironment, which is important for tumor development, growth, proliferation, migration and chemoresistance. Our previous research has shown that macrophages (MΦ) are associated with malignant BM and confer MM cell chemoresistance in vitro. Based on these findings, we designed mechanistic studies to elucidate MΦ-mediated MM chemoresistance. MΦ protected MM cells from different chemotherapeutics, such as bortezomib, doxorubicin, dexamethasone, melphalan, or their combination-induced apoptosis. Cell-to-cell contact was crucial for such protection. Under a coculture condition, MΦ protected MM cells with wide ranging MM/MΦ ratio. Inhibition of phagocytosis did not affect the protection. An experiment examining MM patients' BM showed that MΦ was a dominant accessory cell population in patients' BM. Patients PBMC-derived MΦ or primary MΦ isolated from patient BM had protective activity. Further mechanistic study showed that surface molecules, such as P/E selectins (on MΦ) and their ligand PSGL-1 (on MM cells), were important for MΦ-mediated MM chemoresistance. Blockade antibodies against either P/E selectins or PSGL-1 significantly repressed MΦ-mediated drug resistance. MΦ had limited protection on PSGL-1-knocked down MM cells. Next, we examined intracellular signal transduction in MM cells, upon interaction with MΦs. Src family kinase and Erk1/2 kinase were activated in MM cells, after coculture with MΦs. Coculture also stimulated PSGL-1 and c-myc overexpression in MM cells. Inhibition of Src family kinase, Erk1/2 kinase, or c-myc by small molecule inhibitors impaired MΦ-mediated MM chemoresistance. The overexpression of PSGL-1, under coculture condition, could be repressed by IFN-α neutralization antibody. More importantly, coculture with MΦ could not stimulate Erk1/2 activation or c-myc overexpression in PSGL-1-knocked down MM cells, suggesting that Erk1/2 and c-myc were downstream of PSGL-1-initiated signal transduction. Finally, we established a NOD-SCID mouse model to test MΦ-mediated MM chemoresistance in vivo. MM tumors with MΦ infiltration grew significantly faster than MM, only, tumors and were more resistant to melphalan treatment. Overall, our data demonstrated a mechanism of MΦ-mediated chemoresistance, both in vitro and in vivo. Based on our findings, MΦ-targeted therapy in MM treatment may be beneficial to improve the effectiveness of MM chemotherapy. Disclosures: No relevant conflicts of interest to declare.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V118.21.130.130
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2011
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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