Diagnostic framing of IgM monoclonal gammopathy: Focus on Waldenström macroglobulinemia

Tedeschi, Alessandra; Conticello, Concetta; Rizzi, Rita; Benevolo, Giulia; Laurenti, Luca; Petrucci, Maria Teresa; Zaja, Francesco; Varettoni, Marzia

doi:10.1002/hon.2539

Cited by 11 publications

(12 citation statements)

References 92 publications

(165 reference statements)

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“…While non-IgM MGUS mostly evolves to multiple myeloma (25,(66)(67)(68), IgM MGUS has been increasingly recognized as the premalignant precursor state for WM (23)(24)(25)(26)65). However, to date it has remained challenging to clinically or molecularly distinguish WM from smoldering WM and IgM MGUS (23,(69)(70)(71). Premalignant IgM MGUS and malignant WM cells were found to be phenotypically similar to each other (70).…”

Section: Discussionmentioning

confidence: 99%

B-Cell-Specific Myd88 L252P Expression Causes a Premalignant Gammopathy Resembling IgM MGUS

et al. 2020

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A highly recurrent somatic L265P mutation in the TIR domain of the signaling adapter MYD88 constitutively activates NF-κB. It occurs in nearly all human patients with Waldenström’s macroglobulinemia (WM), a B cell malignancy caused by IgM-expressing cells. Here, we introduced an inducible leucine to proline point mutation into the mouse Myd88 locus, at the orthologous position L252P. When the mutation was introduced early during B cell development, B cells developed normally. However, IgM-expressing plasma cells accumulated with age in spleen and bone, leading to more than 20-fold elevated serum IgM titers. When introduced into germinal center B cells in the context of an immunization, the Myd88L252P mutation caused prolonged persistence of antigen-specific serum IgM and elevated numbers of antigen-specific IgM plasma cells. Myd88L252P-expressing B cells switched normally, but plasma cells expressing other immunoglobulin isotypes did not increase in numbers, implying that IgM expression may be required for the observed cellular expansion. In order to test whether the Myd88L252P mutation can cause clonal expansions, we introduced it into a small fraction of CD19-positive B cells. In this scenario, five out of five mice developed monoclonal IgM serum paraproteins accompanied by an expansion of clonally related plasma cells that expressed mostly hypermutated VDJ regions. Taken together, our data suggest that the Myd88L252P mutation is sufficient to promote aberrant survival and expansion of IgM-expressing plasma cells which in turn can cause IgM monoclonal gammopathy of undetermined significance (MGUS), the premalignant condition that precedes WM.

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Section: Discussionmentioning

confidence: 99%

B-Cell-Specific Myd88 L252P Expression Causes a Premalignant Gammopathy Resembling IgM MGUS

et al. 2020

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“…Most of the IgG standard particles exhibited single mobility, as in lane 9 of Figure 6. The relevance of our findings of IgM sensitivity to certain 5 kD to 20 kD proteins should be explored, especially in patients with Waldenström's macroglobulinemia [5]. Are these patients' sera deficient?…”

Section: Resultsmentioning

confidence: 91%

“…So far, the immunoglobulin M-degrading enzyme of Streptococcus suis is the only known protease cleaving the IgM multimer specifically [4]. The IgM pentamers appears to be an asymmetric pentagon with an open groove that binds the AIM protein, an apoptosis inhibitor of macrophage [5]. Other proteins may bind there and then digest IgM structures.…”

Section: Resultsmentioning

confidence: 99%

Conversion of IgM to IgG by Lysates of Burkitt’s Lymphoma Cells

2021

Trends in Vaccines and Immunology

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“…Additionally, samples from elderly humans are commonly screened by SPE and IF, even if they are normoproteinemic and normoglobulinemic because MGUS is found in 5% of people over 70 years old and is considered a pre-malignant state. 22 The authors feel that the inclusion of these eight cases was warranted in light of current human practices for screening electrophoresis studies that could be reasonably adopted for the evaluation of canine samples in the future. The documentation of a suspected IgM MGUS case in one of these eight cases argues strongly that the study population is a reasonable representation of the target diagnostic pool and that further electrophoresis-based evaluation of normoproteinemic and normoglobulinemic cases is warranted.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic performance of routine electrophoresis and immunofixation for the detection of immunoglobulin paraproteins (M‐Proteins) in dogs with multiple myeloma and related disorders: Part 2—Toward improved diagnostic performance

Moore

Harris

Jeffries

et al. 2021

Veterinary Clinical Pathol

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Background:The diagnostic performance of routine electrophoresis (agarose gel electrophoresis [AGE] and capillary zone electrophoresis [CZE]) and species-specific immunofixation (IF) for the detection of immunoglobulin paraproteins (M-proteins) and diagnosis of secretory myeloma-related disorders (sMRD) can be improved. Available canine IF targets were IgG-FC, IgA, IgM, light chain (LC), IgG4, and free LC (fLC) antibodies. Objective: We aimed to review specific features associated with the presence of M-proteins in canine serum samples and the common features causing inaccurate reporting of M-proteins to improve the diagnostic performance of routine electrophoresis and IF for the detection of M-proteins. Methods: Features found in AGE, CZE, routine IF, IgG4 IF, and fLC IF of 100 canine serum samples from Part 1 of this study were evaluated by simple and multivariate logistic regression to identify factors associated with the presence of M-proteins.Cases falsely called negative or positive for M-proteins were reviewed to identify the common features that could be used to increase the diagnostic performance of SPE and IF for M-protein detection. Results:The presence of hypogammaglobulinemia or any peak taller than albumin was associated with an M-protein. Total protein concentrations, globulin concentrations, or peaks wider than albumin were not associated with an M-protein. Free LC sMRD cases were not diagnosed by SPE and routine IF. Cases with infectious and inflammatory etiologies had a restricted polyclonal gammopathy with multiple γglobulin restrictions resulting in some false-positive results. SPE combined with all available IF results and the specific features identified in this study had an estimated sensitivity of 95.1% and specificity of 81.4%. Conclusions:The identified criteria of this study increase the diagnostic performance of the electrophoretic evaluation for M-proteins.

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Diagnostic framing of IgM monoclonal gammopathy: Focus on Waldenström macroglobulinemia

Cited by 11 publications

References 92 publications

B-Cell-Specific Myd88 L252P Expression Causes a Premalignant Gammopathy Resembling IgM MGUS

B-Cell-Specific Myd88 L252P Expression Causes a Premalignant Gammopathy Resembling IgM MGUS

Conversion of IgM to IgG by Lysates of Burkitt’s Lymphoma Cells

Diagnostic performance of routine electrophoresis and immunofixation for the detection of immunoglobulin paraproteins (M‐Proteins) in dogs with multiple myeloma and related disorders: Part 2—Toward improved diagnostic performance

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