Clonal evolution of myeloma cells leads to quantitative changes in immunoglobulin secretion and surface antigen expression.

Leibson, Paul J.; Loken, Michael R.; Panem, Sandra; Schreiber, Hans

doi:10.1073/pnas.76.6.2937

Cited by 21 publications

(16 citation statements)

References 35 publications

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“…The original clone may persist as single clone, but probably more often subclones with truncated ability for production of intact immunoglobulins do emerge. 29, 30 They may produce light chains, or as shown in some patients in our study, intact immunoglobulins (heavy and light chains) only, and may coexist with the original population of intact molecule secreting myeloma cells. Thus, the HLC assay likely will provide additional information on the clonal evolution in myeloma.…”

Section: Discussionsupporting

confidence: 60%

Immunoglobulin heavy/light chain ratios improve paraprotein detection and monitoring, identify residual disease and correlate with survival in multiple myeloma patients

et al. 2012

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The novel heavy/light chain (HLC) assay was used for the detection and measurement of monoclonal immunoglobulins, response evaluation and prognostication. This test allows identification and quantification of the different light chain types of each immunoglobulin class (for example, IgGκ and IgGλ) and enables calculation of ratios of monoclonal/polyclonal immunoglobulin (HLC ratio). Sequential sera of 156 patients with IgG or IgA myeloma started on first-line therapy and followed for a median of 46.1 months were analyzed. Results were compared with those obtained with conventional techniques (serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE), nephelometry (NEPH), and the free light chain test (FLC)). Our data show that the HLC assay allowed quantification of monoclonal proteins not accurately measurable by SPEP or NEPH. When both HLC and FLC testing were applied for response assessment, clonal excess was noted in 14/31 patients with complete response (CR). HLC ratio indicated presence of disease in 8/31 patients who achieved CR and, in sequential studies indicated evolving relapse in three patients before IFE became positive. Highly abnormal HLC ratios at presentation were significantly associated with shorter overall survival (40.5 months vs median not reached, P=0.016). Multivariate analysis revealed HLC ratio (P=0.03) and β2-microglobulin (P<0.01) as independent risk factors for survival.

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Section: Discussionsupporting

confidence: 60%

Immunoglobulin heavy/light chain ratios improve paraprotein detection and monitoring, identify residual disease and correlate with survival in multiple myeloma patients

et al. 2012

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“…The flow-cytometry DNA studies show the plasmacytoma cells to be near tetraploid. a finding which has been noted by others examining plasmacytomas by either karyotype analysis (Yoshida, Imai & Potter, 1968) or flow cytometry (Leibson et al, 1979).…”

Section: Discussionsupporting

confidence: 63%

Analysis of Mopc‐315 Plasmacytoma By Elutriation and Flow Cytometry

Flentje

Valeriote

et al. 1984

Cell Proliferation

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Intravenously transplanted murine plasmacytoma MOPC‐315 cells were separated from normal spleen cells from a tumour‐bearing mouse by elutriation and characterized according to morphology, immunologic properties and clonogenicity. Morphologically, both lymphocytoid and plasmacytoid cells were separable by elutriation. Flow cytometry correlated DNA content and intracytoplasmic IgA content and demonstrated two distinct populations, both in cell cycle, but with markedly different cellular IgA levels. Density gradient separation characterized the lower‐density cells with lower IgA content and higher clonogenicity. From these studies a model of cellular differentiation is proposed.

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“…In the secretory rate maturation hypothesis, memory B cells divide and differentiate, with σ IgG increasing with each cell division until a maximum rate is reached. This mechanism seems plausible as IgG secreting B cell blasts, plasma cells and hybridoma clones exhibit heterogeneity of IgG secretion rates (5-8). A competing hypothesis is that antibody secretion is controlled by a stochastic binary “On/Off” switch, in which all B cells secreting IgG do so at a rate ( σ IgG ) which is fixed irrespective of the number of post-activation cell divisions or other factors (9, 10).…”

Section: Introductionmentioning

confidence: 99%

Modulation of Single-Cell IgG Secretion Frequency and Rates in Human Memory B Cells by CpG DNA, CD40L, IL-21, and Cell Division

Henn¹,

Rebhahn²,

Brown³

et al. 2009

The Journal of Immunology

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During the recall response by CD27+ IgG class-switched human memory B cells, total IgG secreted is a function of the following: 1) the number of IgG-secreting cells (IgG-SC), and 2) the secretion rate of each cell. In this study, we report the quantitative ELISPOT method for simultaneous estimation of single-cell IgG secretion rates and secreting cell frequencies in human B cell populations. We found that CD27+ IgM− memory B cells activated with CpG and cytokines had considerable heterogeneity in the IgG secretion rates, with two major secretion rate subpopulations. BCR cross-linking reduced the frequency of cells with high per-cell IgG secretion rates, with a parallel decrease in CD27high B cell blasts. Increased cell death may account for the BCR-stimulated reduction in high-rate IgG-SC CD27high B cell blasts. In contrast, the addition of IL-21 to CD40L plus IL-4-activated human memory B cells induced a high-rate IgG-SC population in B cells with otherwise low per-cell IgG secretion rates. The profiles of human B cell IgG secretion rates followed the same biphasic distribution and range irrespective of division class. This, along with the presence of non-IgG-producing, dividing B cells in CpG plus cytokine-activated B memory B cell populations, is suggestive of an on/off switch regulating IgG secretion. Finally, these data support a mixture model of IgG secretion in which IgG secreted over time is modulated by the frequency of IgG-SC and the distribution of their IgG secretion rates.

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Clonal evolution of myeloma cells leads to quantitative changes in immunoglobulin secretion and surface antigen expression.

Abstract: We report that a cloned population of tumor cells can rapidly produce variants

Cited by 21 publications

References 35 publications

Immunoglobulin heavy/light chain ratios improve paraprotein detection and monitoring, identify residual disease and correlate with survival in multiple myeloma patients

Immunoglobulin heavy/light chain ratios improve paraprotein detection and monitoring, identify residual disease and correlate with survival in multiple myeloma patients

Analysis of Mopc‐315 Plasmacytoma By Elutriation and Flow Cytometry

Modulation of Single-Cell IgG Secretion Frequency and Rates in Human Memory B Cells by CpG DNA, CD40L, IL-21, and Cell Division

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