Dominant role of CD47–thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease

Kukreja, Anjli; Radfar, Soroosh; Sun, Ben‐hua; Insogna, Karl L.; Dhodapkar, Madhav V.

doi:10.1182/blood-2009-03-211920

Cited by 70 publications

(70 citation statements)

References 52 publications

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“…CD47 on myeloma cells also interacts with TSP-1 on immature dendritic cells (iDCs) and, it has been reported, induces the differentiation of the iDCs into multinuclear osteoclast-like cells. 40 An anti-TSP-1 antibody blocking the interaction of CD47 and TSP-1 abolished the differentiation of iDCs to osteoclast-like cells. Therefore, blockade of CD47 with anti-CD47 antibodies may abolish the interaction with TSP-1 and inhibit the formation of osteoclast-like cells and reduce bone resorption in patients.…”

Section: Discussionmentioning

confidence: 99%

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Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

et al. 2012

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Multiple myeloma is a plasma cell neoplasm residing in bone marrow. Despite advances in myeloma therapies, novel therapies are required to improve patient outcomes. CD47 is highly expressed on myeloma cells and a potential therapeutic candidate for myeloma therapies. Flow cytometric analysis of patient bone marrow cells revealed that myeloma cells overexpress CD47 when compared with non-myeloma cells in 73% of patients (27/37). CD47 expression protects cells from phagocytosis by transmitting an inhibitory signal to macrophages. Here we show that blocking CD47 with an anti-CD47 monoclonal antibody increased phagocytosis of myeloma cells in vitro. In xenotransplantation models, anti-CD47 antibodies inhibited the growth of RPMI 8226 myeloma cells and led to tumor regression (42/57 mice), implicating the eradication of myeloma-initiating cells. Moreover, anti-CD47 antibodies retarded the growth of patient myeloma cells and alleviated bone resorption in human bone-bearing mice. Irradiation of mice before myeloma cell xenotransplantation abolished the therapeutic efficacy of anti-CD47 antibodies delivered 2 weeks after radiation, and coincided with a reduction of myelomonocytic cells in spleen, bone marrow and liver. These results are consistent with the hypothesis that anti-CD47 blocking antibodies inhibit myeloma growth, in part, by increasing phagocytosis of myeloma cells.

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Section: Discussionmentioning

confidence: 99%

“…In addition to acting as a 'don't eat me' signal, Kukreja et al 40 have suggested a role of CD47 in osteoclastogenesis. CD47 on myeloma cells also interacts with TSP-1 on immature dendritic cells (iDCs) and, it has been reported, induces the differentiation of the iDCs into multinuclear osteoclast-like cells.…”

Section: Discussionmentioning

confidence: 99%

Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

et al. 2012

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“…In addition, CD47 has been suggested to function as a receptor for thrombospondin (8), and as a ligand for signal regulatory protein ␣ (SIRP␣) (9). SIRP␣ is also an Ig superfamily cell surface glycoprotein shown to be highly expressed in myeloid cells, neurons, endothelial cells, and fibroblasts, but not by T cells or B cells.…”

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confidence: 99%

Lack of CD47 Impairs Bone Cell Differentiation and Results in an Osteopenic Phenotype in Vivo due to Impaired Signal Regulatory Protein α (SIRPα) Signaling

Koskinen

Persson

Baldock

et al. 2013

Journal of Biological Chemistry

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Background: CD47 and its receptor SIRP␣ are suggested to regulate bone metabolism. Results: Lack of CD47 prevents stromal cell SIRP␣ signaling, which impairs bone marrow stromal cell differentiation, subsequent osteoclast differentiation, and bone homeostasis. Conclusion: CD47 and SIRP␣ both mediate normal bone cell and bone tissue formation. Significance: CD47/SIRP␣ may be a future molecular target to modulate bone homeostasis.

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“…DCs are known to be enriched in several human tumors, including MM, and are primarily studied for their effects on tumor immunity, growth regulation, or osteoclastogenesis but not direct effect on genetics of tumors. [8][9][10][11]18,[24][25][26][27] AID can also play an important role in the development of chromosome translocations (particularly those involving the IgH locus), oncogenic mutations, as well as DNA demethylation that may contribute to carcinogenesis. 21,28 AID may also be important for murine myeloma models.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell–mediated activation-induced cytidine deaminase (AID)–dependent induction of genomic instability in human myeloma

Koduru¹,

Wong²,

Strowig³

et al. 2012

Blood

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Tumor microenvironment (TME) is commonly implicated in regulating the growth of tumors, but whether it can directly alter the genetics of tumors is not known. IntroductionMultiple myeloma (MM) is characterized by the growth of malignant plasma cells in the BM. Genomic instability and chromosome translocations are common and early hallmarks of this tumor. 1 In particular, aneuploidy as well as chromosome translocations that involve the immunoglobulin heavy chain (IgH) locus are commonly observed in MM as well as its precursor monoclonal gammopathy of undetermined significance. However, the mechanisms underlying genomic instability in MM or monoclonal gammopathy of undetermined significance are poorly understood. One candidate is activation-induced cytidine deaminase (AID), which is essential for somatic hypermutation and class switch recombination. 2,3 Mistargeting of AID has been implicated in oncogenic mutations and chromosome translocations in both lymphoid and nonlymphoid tumors. [3][4][5] However, prior studies have failed to detect AID in MM cell lines, implying that other pathways may be involved in mediating genomic instability in this tumor. 6 Several studies have emphasized the importance of tumor microenvironment (TME) in the biology of human MM. 7 Although the role for TME in regulating tumor growth is well established, whether and how it might directly alter the genetics of tumors are not known. Several studies have shown that tumor lesions in MM are highly infiltrated by dendritic cells (DCs). [8][9][10] In prior studies we had observed that the interaction between DCs and MM cells led to aberrant reexpression of BCL6 in MM cells, a gene typically silenced during normal plasma cell differentiation. 11 Therefore, we tested whether this interaction could also induce the expression of AID in tumor cells. Methods Tumor cell lines and patient samplesMM cell lines were purchased from ATCC (U266), or kindly provided by Dr Joshua Epstein (Little Rock, AR; OPM2, ARK, and CAG cells). Other tumor cells used were MCF-7 cells (breast cancer; gift from Dr Lyndsay Harris, Yale Cancer Center). Cells were cultured in RPMI 1640 with 10%-15% FBS. BM and peripheral blood specimens were obtained from patients with myeloma after informed consent was obtained in accordance with the Declaration of Helsinki under a protocol approved by the institutional review board of Yale University. Peripheral blood buffy coats from healthy donors were purchased from the New York Blood Center. Isolation of mononuclear cells, DCs, primary tumor cells, and DC subsetsPeripheral blood or BM mononuclear cells (MNCs) were isolated by density gradient centrifugation (Ficoll-Paque plus; Amersham Biosciences). DCs were generated from purified blood monocytes as described earlier. 11,12 In brief, monocytes isolated with CD14 microbeads (Miltenyi Biotec) were cultured in the presence of GM-CSF (20 ng/mL; Genzyne) and IL-4 (20 ng/mL; R&D Systems). DCs were typically used on day 5 or 6 of culture. For some experiments, DCs were matured by the use of...

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Dominant role of CD47–thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease

Cited by 70 publications

References 52 publications

Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

Lack of CD47 Impairs Bone Cell Differentiation and Results in an Osteopenic Phenotype in Vivo due to Impaired Signal Regulatory Protein α (SIRPα) Signaling

Dendritic cell–mediated activation-induced cytidine deaminase (AID)–dependent induction of genomic instability in human myeloma

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