Plasma cell differentiation and multiple myeloma

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Abstract

Microarray analyses and gene targeting have recently enhanced the understanding of factors involved in normal plasma cells and multiple myeloma. Plasma cells develop from marginal zone or germinal center B cells following stimulation by antigen, microbial products, TNF family signals and cytokines. Transcription factors, B-lymphocyte-induced maturation protein 1 (Blimp-1) and X-box binding protein 1 (XBP-1) are required for plasma cell development. They regulate sets of genes that induce immunoglobulin secretion, halt proliferation and block alternative B-cell fates. In multiple myeloma, transforming events lead to proliferation and survival, but programs for plasma cell differentiation and the inhibition of B-cell genes appear to be largely intact.

Introduction

The mature effectors of the B-cell lineage are terminally differentiated non-dividing plasma cells (PCs), dedicated to secreting copious amounts of antibody [1]. Antigen, in combination with other signals, triggers naı̈ve B cells in the splenic marginal zone (MZ) to proliferate and differentiate into mainly short-lived PCs secreting low affinity IgM as the first antibody response to pathogens [1]. Subsequently, antigen and antigen-specific T helper (Th) cells cause naı̈ve follicular B cells to undergo proliferation, affinity maturation and isotype switch recombination in a germinal center (GC) reaction. This reaction ultimately produces PCs secreting high affinity antibody with predominantly switched isotypes [2]. If PCs receive survival signals from stromal cells, usually in the bone marrow (BM) but possibly in the spleen [3], they survive for many months [4].

In addition to their critical role in normal immunity, PCs are also involved in disease. Multiple myeloma (MM) results from malignant transformation of PCs or their precursors [5], and long-lived PCs are important in antibody-dependent autoimmune diseases. Recent studies have begun to identify signaling pathways and transcriptional regulators that are required for a B cell to make the decision to develop into a PC. One goal of such studies is to provide a basis for the rational design of therapeutic agents to block the activity of PCs in autoimmunity and MM. With this in mind, this review focuses on recent advances in understanding molecular controls in both normal PCs and MM.

Section snippets

Signals that promote plasma-cell formation

Multiple TNF superfamily proteins are important for PC differentiation. Signaling through the lymphotoxin pathway is required for the spatial and temporal organization of various lymphoid tissues in which PCs develop: Peyer’s patches, splenic MZ and follicular dendritic cell (DC) networks in GCs 6., 7.. In addition, B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), and their receptors transmembrane activator and CAML interactor (TACI), B-cell maturation antigen (BCMA)

B-lymphocyte-induced maturation protein 1

The transcriptional repressor B-lymphocyte-induced maturation protein 1 (Blimp-1) is induced upon PC differentiation and is sufficient to drive B cells to become Ig-secreting PCs [1]. Recently, the conditional deletion of the gene for Blimp-1, prdm1, in B cells has shown that Blimp-1 is also required for PC development [27••]. In mice lacking Blimp-1, severe deficits were observed in early PCs formed from MZ B cells in response to both T-cell-independent and -dependent antigens, PCs formed

Long-lived plasma cells

Long-lived PCs, particularly those in the BM, are intriguing mechanistically and are important in disease states as well as normal immunity. These cells are antigen-independent [41], but require survival signals via IL-6 and other factors 23.•, 42.•. Interestingly, these long-lived PCs are not formed in early life [43] and they decrease with aging [44]. It will be interesting to learn if these PCs still require Blimp-1 and/or XBP-1 for their continued survival and function, and whether by

Gene expression in plasma cells

cDNA microarrays have become a valuable tool for analyzing gene expression in PCs and their precursors. Arrays using PCs from murine lymph node (LN) and human tonsil and BM confirmed the induction of Blimp-1 and XBP-1, and the repression of Pax5 and other Blimp-1 targets in PCs 45., 46.••. Interestingly, some gene expression patterns were different from those observed during previous microarray studies on B-cell lymphoma lines expressing ectopic Blimp-1 [29••]. These differences may be

Gene expression in multiple myeloma

MM is a fatal PC neoplasm associated with anemia, osteolytic bone lesions, renal failure and immunodeficiency, reviewed in [54]. MM cells can have multiple chromosomal abnormalities and complex translocations. Translocations often fuse the IgH locus to cyclin D1, cyclin D3, c-maf, FGFR3 (fibroblast growth factor receptor 3), MMSET (multiple myeloma SET domain), IRF4, or myc genes, and misregulation of these genes is thought to be important for malignant transformation. Activation of ras and

Conclusions

Although for many years the biology of both normal PCs and MM was poorly understood, recently there has been remarkable progress. The pace and trajectory of work in this field provides strong hope for continued, rapid progress in the future and, perhaps, development of treatments to control these cells in disease.

We now understand that, in addition to antigen, other molecules critically influence the terminal differentiation of B cells to Ig-secreting plasma cells. These include TNF family

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

The authors would like to thank members of the Calame laboratory and Michael McHeyzer-Williams for helpful discussions. This work was supported by AI50659 and AI43576.

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