Malignant plasma cell lines express a functional CD28 molecule

Zhang, X G; Olive, Daniel; Vos, John De; Rebouissou, Cosette; Ghiotto-Ragueneau, Marguerite; Ferlin, Martine; Klein, Bernard

doi:10.1038/sj.leu.2400971

Cited by 31 publications

(26 citation statements)

References 11 publications

(26 reference statements)

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“…Alternatively, different actions of receptors depending on the cell type specific expression are shown, which might also hold true for CTLA-4 on B cells. This is exemplified by B7-2 molecules on T cells, (16) or CD28 on plasma cells (22,56). As our research has demonstrated that already intracellular trafficking of CTLA-4 to the cell surface differs between T and B cells, we favor the notion that initiated signaling pathways of CTLA-4 might differ also between T and B cells.…”

Section: Discussionmentioning

confidence: 78%

A New Role of CTLA-4 on B Cells in Thymus-Dependent Immune Responses In Vivo

Quandt

Hoff

Rudolph

et al. 2007

The Journal of Immunology

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The expression of CTLA-4 (CD152) on the cell surface of B cells and its consequences for the humoral immune response in vivo are unknown. We investigated the expression of CTLA-4 mRNA and protein in B cells in T cell-independent or -dependent ways. B cells in the presence of Ag-stimulated Th2 cells expressed mRNA of CTLA-4 and up-regulated intracellular CTLA-4 protein. Using a liposome-enhanced staining technique, we show for the first time, that surface CTLA-4 protein is expressed by 11–15% of B cells in a T cell-dependent culture system. To dissect the role of CTLA-4 on B cells in vivo, we used bone marrow chimeric mice in which only B cells were CTLA-4 deficient. These mice showed that early B cell development and homeostasis is not influenced by CTLA-4 deficiency of B cells. Ag-specific responses after immunization of the chimeric mice revealed elevated levels of IgM Abs in mice deficient for B cell CTLA-4. We propose that CTLA-4 signals on B cells determine the early fate of B cells in thymus-dependent immune responses.

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Section: Discussionmentioning

confidence: 78%

A New Role of CTLA-4 on B Cells in Thymus-Dependent Immune Responses In Vivo

Quandt

Hoff

Rudolph

et al. 2007

The Journal of Immunology

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“…In addition, the possibility that CD28 is involved in the progression to stroma-independent MM is supported by observations that primary CD28 ϩ myelomas coexpress CD86 (10 of 10 patient samples in Robillard et al 12 ) and that CD86 ϩ myelomas have a significantly poorer prognosis. 25 The possibility of autocrine CD28-CD86 activation is supported by some, 13 but not all, 26 in vitro studies. Other functional studies of CD28 activation in MM cell lines have been equivocal.…”

Section: Introductionmentioning

confidence: 82%

“…Other functional studies of CD28 activation in MM cell lines have been equivocal. 10,13 CD28 activation does not induce IL-6 secretion in MM cells 22,26 like it does in T cells, 27 but does up-regulate expression of the proangiogenic chemokine IL-8. 22 Direct evidence of a prosurvival role for CD28 in myeloma cells has not been reported, although such a role in normal plasma cells is indirectly suggested by our previous observations that CD28 knockout mice have markedly diminished serum immunoglobulin levels, 18,28 including T-independent antibody responses.…”

mentioning

confidence: 99%

CD28-mediated regulation of multiple myeloma cell proliferation and survival

Bahlis

King

Kolonias

et al. 2007

Blood

119

115

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Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NFB, suppresses MM cell proliferation, and protects against serum starvation and dexamethasone (dex)-induced cell death. Coculture with dendritic cells (DCs) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DCs appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma/DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of MM. IntroductionMultiple myeloma (MM) remains an incurable clonal B lymphoid neoplasm of plasma cells, second only to non-Hodgkin lymphoma in incidence. 1 Despite significant initial responses to chemotherapy, more than 90% of patients with MM relapse with resistant disease, 2 underscoring the need to identify novel therapeutic targets that affect myeloma survival and resistance pathways. Given that MM cells are critically dependent on normal elements of the bone marrow stroma for cell growth and survival, these interactions are attractive targets. One such interaction is stromal production of soluble growth factors, such as IL-6 and TRANCE. 1,3 Another important set of interactions involves direct myeloma cell contact with extracellular matrix (ECM) and/or stromal cells. Such direct contact up-regulates stromal cell IL-6 and VEGF production, induces NFB signaling, drops myeloma cells out of cell cycle, and enhances resistance to chemotherapy. [4][5][6] However, the specific molecular (eg, integrins 4,7 ) and cellular components (eg, osteoclasts 8 ) of these direct interactions within the complex bone marrow microenvironment are only beginning to be described. As important, the characteristic progression of myeloma to stromal independence marks a clinically worse disease, 9 yet the mechanisms that underlie this transition are also poorly understood.Identification of prosurvival receptors typically expressed on myeloma cells may point to the stromal cells expressing the receptor ligands. One potential receptor is CD28. CD28 has a restricted lineage expression, found predominantly on T cells but also on normal plasma cells, primary myeloma isolates, and myeloma cell lines at levels comparable with T cells. [10][11][12][13] In T cells, CD28 recep...

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“…23 Of note, although we and others were unable to define a function of CD28 on myeloma cells, this molecule is clearly functional. 13,24 Finally, the mechanisms involved in the upregulation of CD28, as those involved in that of CD56, remain unknown.…”

Section: Discussionmentioning

confidence: 99%

The absence of CD56 (NCAM) on malignant plasma cells is a hallmark of plasma cell leukemia and of a special subset of multiple myeloma

et al. 1998

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In this study, we show that malignant plasma cells from patients with either primary (n = 12) or secondary (n = 15) plasma cell leukemia (PCL) do not express CD56 at all, neither in the bone marrow nor the peripheral blood in 81% of cases. On the other hand, multiple myeloma (MM) at diagnosis overexpress it in 63 of 94 (67%) cases (P = 0.0001). In three secondary PCL evaluated serially, CD56 was also lacking at diagnosis showing that CD56 is not downregulated at the end stage of the disease but rather not upregulated in this subset of patients. This last concept is strengthened by the observation that 29% of MM patients lacking CD56 or weakly expressing it at diagnosis present a detectable leukemic phase vs 11% only in CD56 + MM (P = 0.06). Forty percent of all the CD56 −/weak malignant plasma cell disorders present or develop a leukemic phase vs only 15% of CD56 + cases (P Ͻ 0.008). CD56 −/weak MM subset is also associated with a significantly less aggressive osteolytic potential (P = 0.012). We conclude that the lack or weak expression of CD56 is a characteristic feature of PCL but also delineates a special subset of MM at diagnosis mainly characterized by a lower osteolytic potential and a trend for malignant plasma cells to circulate in the peripheral blood more overtly.

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Malignant plasma cell lines express a functional CD28 molecule

Cited by 31 publications

References 11 publications

A New Role of CTLA-4 on B Cells in Thymus-Dependent Immune Responses In Vivo

A New Role of CTLA-4 on B Cells in Thymus-Dependent Immune Responses In Vivo

CD28-mediated regulation of multiple myeloma cell proliferation and survival

The absence of CD56 (NCAM) on malignant plasma cells is a hallmark of plasma cell leukemia and of a special subset of multiple myeloma

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