Cellular Development

Lymphoid cells are derived from a common lymphoid progenitor which has the capacity to develop into a T, B, or natural killer cell.1 The first recognizable B-cell type is a pro-B cell, which develops under the influence of transcription factors essential for B-cell commitment. The pro-B cell expresses the characteristic B-

Figure 81.4 Binucleated plasma cell in a patient with myeloma

Figure 81.5 Plasmablasts with prominent nucleoli in a patient with plasma cell leukemia cell surface marker CD 19, but not cytoplasmic ^ immunoglobulin. It undergoes rearrangement of the Ig heavy-chain (IgH) genes, the product of which associates with that of the variable pre-beta and lambda 5 genes, which encode proteins forming the surrogate light chain. Subsequent rearrangement of true light-chain genes enables expression of surface IgM. The immature B cell thus expresses CD19, as well as cell surface IgM associated with kappa or lambda light chains, i.e., the B-cell receptor. A virgin B cell is an IgM+, IgD+ cell that circulates in the peripheral blood in the G0 phase of cell cycle. It may be activated to proliferate and produce plasma cells and memory B cells. Such activation requires contact with T cells.

B cells with high-affinity receptors receive survival signals from antigen stimulation on dendritic cells and differentiate into memory B cells or plasmablasts, which subsequently migrate to the bone marrow and develop into plasma cells. These bone marrow plasma cells have a long life span and produce the majority of secreted Ig in the plasma. They are considered to be the normal, nonmalignant counterpart of the MPC.

MOLECULAR ASPECTS OF PLASMA CELL DEVELOPMENT IgH gene rearrangements and V gene usage in myeloma

Maturation of normal B-cell precursors to mature plasma cells involves rearrangement of the Ig genes with subsequent somatic mutation of the variable (V) region. The variable region of the Ig heavy chain is derived from three distinct gene segments encoded by the variable (V), diversity (D), and joining (J) region sequences. For the light chain, the variable region is composed of variable kappa or lambda gene segments linked to the joining segments. V gene rearrangement is dependent on the protein products of recombinase activating genes. Within the variable regions of both the Ig heavy- and light-chain genes, there are three hypervariable or complementary determining regions (CDR). These unique segments can be used as markers to detect minimal residual disease in B-cell tumors. CDR3 is the most variable portion of the Ig molecule, and is the principal site for somatic mutation and antibody affinity maturation of the Ig molecule.14

After variable region recombination, the isotypes of the heavy chains are determined by a process known as isotype switching. Many of the chromosomal translocations seen in multiple myeloma occur in these switch regions. The process of VDJ rearrangement and class switching allows a single B-cell clone to produce antibodies of different heavy-chain classes to the same antigenic epitope. The rearrangement of Ig genes during B-cell development is sequential, occurring at distinct stages of development. Heavy-chain genes undergo rearrangement before the light-chain genes. The product of successful heavy-chain VDJ joining activates rearrangements of the kappa locus, which precedes lambda rearrangement.

In myeloma, the malignant plasma cells have already undergone somatic mutation within the germinal center, and no ongoing mutation occurs with progressive disease. Thus, the mutation mechanism is no longer active in the malignant clone.1516 Analysis of the variable genes has indicated that the majority of the malignant population is derived from a post-antigen-selected plasma cell. However, less mature, minor B-cell populations of identical variable gene sequences may coexist in the circulation, both in the postswitch and preswitch populations.17

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