Distinctive Features of Immunoglobulin Heavy Chain Variable Region Gene Rearrangement in Multiple Myeloma

Abstract

We have analysed the rearranged Ig heavy chain (IgH) genes in a series of 28 cases of multiple myeloma (MM), in order to extend the study of Ig heavy chain variable (VH) gene usage in B lymphoid malignancies and to explore the ontogenic compartment from which transformed precursor cells arise in this disease. We were able to amplify 28 rearranged alleles by polymerase chain reaction from 23 of these cases, using a common joining region (JH) amplimer together with a panel of VH family-specific amplimers. The pattern of VH family usage was similar to that reported in normal peripheral blood B cells with infrequent usage of VH5 and VH6 genes. However, nucleotide sequence analysis of 17 IgH alleles revealed rearrangement of other VH family members, closely related to known developmentally regulated VH genes, some of which are known to be associated with autoimmune specificities. In contrast to previous findings on more immature B lineage malignancies, the rearranged genes diverged extensively from consensus germline sequences, consistent with somatic mutation. These findings support the hypothesis that the major proliferating precursor in MM arises at, or following a stage of T cell-dependent germinal centre proliferation in lymphoid follicles.

High Frequency of Clonal Immunoglobulin Receptor Gene Rearrangements in Sporadic Histiocytic/Dendritic Cell Sarcomas

“…4,13,14,21,31,34,39,44,47 It has been hypothesized that B-cell receptors encoded by certain VH gene segments may predispose those B cells to malignant transformation as they may have a greater tendency or capacity to proliferate more frequently because of the recognition of many self-antigens or nonself-antigens. 3,29,41 Our results did not show any obvious differences of VH and JH segment usages between the H/DC sarcoma and the majority of functional B cells.…”

Lymphoma and the Control of B Cell Growth and Differentiation

“…V-region genes of human B-cell lymphomas have been proven to be somatically mutated in most cases, indicating that they originate from GC or post GC B cells. These include certain Hodgkin's diseases (HD) [97][98][99][100], follicular lymphomas (FL) [101,102], Burkitt's lymphomas (BL) [103][104][105][106][107], various diffuse large B-cell lymphomas (DLBCL) [108][109][110], MALT lymphomas [111][112][113][114][115], lymphoplasmacytoid lymphoma (LDL) [116,117], and multiple myeloma (a tumor of plasma cell) [118,119]. One exception is some of the classic Hodgkin's lymphomas where ongoing mutations were not observed due to the introduction of stop codons into the originally functional V-region gene rearrangements [100,120].…”

Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis

“…4 The CDR3 sequence is unique to each rearrangement and therefore identifies individual B cells or clonal B-cell expansion. 4,14,15 The V H D H J H gene repertoires are restricted and developmentally regulated at early stages of differentiation. 3,16 In the most immature B-cell precursors (pro-B cells), the IgH genes remain germ line or there is only D H J H joining.…”

“…[16][17][18] Previous studies have demonstrated a preferential usage of specific V H genes in B-cell malignancies. 15,22,23 In mantle cell lymphoma, V H 3-21, V H 3-23, V H 4-34, V H 4-59, and V H 5-51 segments have shown to be most widely used. 24,25 In B-cell chronic lymphocytic leukemia (CLL), patients with unmutated compared with somatically mutated V H genes have a worse prognosis.…”