Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire

Abstract

The study of immunoglobulin genes in multiple myeloma over the last decade has provided important information regarding biology, ontogenetic assignment, disease evolution, pathogenic consequences and tumor-specific therapeutic intervention. Detailed analysis of V H genes has revealed the clonal relationship between switch variants expressed by the bone marrow plasma cell and myeloma progenitors in the marrow and peripheral blood.

A frequent target of paraproteins in the sera of patients with multiple myeloma and MGUS

“…Epitope specificity was also determined by ELISA using recombinant full-length paratarg-7 and recombinant fragments of paratarg-7 as a coat. All 29 paratarg-7 reactive paraproteins were tested by this ELISA and all reacted with recombinant paratarg-7 1-36 and paratarg-7 [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] confirming the epitope specificity obtained with the peptide spot assay (Fig. 4).…”

“…The observed diversity and the fact that the respective targets were detected by paraproteins from patients who did not have any signs of chronic antigenic stimulation, let us conclude that the role of chronic antigenic stimulation in the pathogenesis of MGUS and MM had probably been overestimated in the past. The view that many-if not any-auto-, allo-and heteroantigenreactive B-cell clones can become the random target of malignant transformation was also supported by the fact that there is no convincing evidence for the preferential use of V genes in MGUS and MM, 25,26 which contrasts with the selective immunoglobulin V gene use in other B-cell malignancies, e.g., marginal zone lymphomas associated with chronic infection and/or autoimmunity. 27 However, in this follow-up study using a fetal-brain derived protein macroarray that had not been included in our first studies, we are now confronted with a paraprotein target that reacts with 15% of all paraproteins analyzed.…”

Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma

“…Multiple myeloma represents a malignancy of the immune system characterized by the presence of a continuously differentiating population of mainly late stage B cells giving rise to plasma cells. 18 The analysis of variable heavy chain (V H ) Leukemia region gene rearrangements in MM indicates that, before transformation, the malignant stem cell (whose exact origin remains elusive) has already undergone antigen selection with consistent lack of intraclonal diversification. 19,20 In our series, analysis of LC V region genes has revealed somatic hypermutation of almost the same magnitude as that reported by others for V H genes.…”

Identification of antigenic targets of paraproteins by expression cloning does not support a causal role of chronic antigenic stimulation in the pathogenesis of multiple myeloma and MGUS

“…Thus, this unbiased systematic study lends support to the view that the role of chronic antigenic stimulation in the pathogenesis of MGUS and MM has probably been overestimated in the past. The view that many-if not any-auto-, allo-and heteroantigen-reactive B-cell clones can become the random target of malignant transformation is also supported by the fact that there is no convincing evidence for the preferential use of V genes in MGUS and MM, 17,18 which contrasts with the selective immunoglobulin V gene use in other B-cell malignancies, e.g., marginal zone lymphomas associated with chronic infection or autoimmunity. 19 The knowledge of the antigenic target structures of paraproteins allows to address in more detail tumor-host interactions in the presence and absence of specific antigens in the respective patients, and to study more specifically the role of immunoregulatory deficiencies, such as the recently reported dysfunction of regulatory T cells 20 in patients with MGUS and multiple myeloma.…”