Normal serum protein electrophoresis and mutated <scp>IGHV</scp> genes detect very slowly evolving chronic lymphocytic leukemia patients

Chauzeix, Jasmine; Laforêt, Marie-Pierre; Devéza, Mélanie; Crowther, Liam P.; Marcellaud, Elodie; Derouault, Paco; Lia, Anne‐Sophie; Boyer, François; Bargues, Nicolas; Olombel, Guillaume; Jaccard, Arnaud; Feuillard, Jean; Gachard, Nathalie; Rizzo, David M.

doi:10.1002/cam4.1510

Cited by 6 publications

(7 citation statements)

References 37 publications

(42 reference statements)

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“…Serum was obtained from blood collected retro-orbitally. Specific ELISA and serum electrophoresis assay were performed as previously described ( 19 , 22 ).…”

Section: Methodsmentioning

confidence: 99%

Continuous MYD88 Activation Is Associated With Expansion and Then Transformation of IgM Differentiating Plasma Cells

et al. 2021

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Activating mutations of MYD88 (MYD88L265P being the far most frequent) are found in most cases of Waldenström macroglobulinemia (WM) as well as in various aggressive B-cell lymphoma entities with features of plasma cell (PC) differentiation, such as activated B-cell type diffuse large B-cell lymphoma (DLBCL). To understand how MYD88 activation exerts its transformation potential, we developed a new mouse model in which the MYD88L252P protein, the murine ortholog of human MYD88L265P, is continuously expressed in CD19 positive B-cells together with the Yellow Fluorescent Protein (Myd88L252P mice). In bone marrow, IgM B and plasma cells were expanded with a CD138 expression continuum from IgMhigh CD138low to IgMlow CD138high cells and the progressive loss of the B220 marker. Serum protein electrophoresis (SPE) longitudinal analysis of 40 Myd88L252P mice (16 to 56 weeks old) demonstrated that ageing was first associated with serum polyclonal hyper gammaglobulinemia (hyper Ig) and followed by a monoclonal immunoglobulin (Ig) peak related to a progressive increase in IgM serum levels. All Myd88L252P mice exhibited spleen enlargement which was directly correlated with the SPE profile and was maximal for monoclonal Ig peaks. Myd88L252P mice exhibited very early increased IgM PC differentiation. Most likely due to an early increase in the Ki67 proliferation index, IgM lymphoplasmacytic (LP) and plasma cells continuously expanded with age being first associated with hyper Ig and then with monoclonal Ig peak. This peak was consistently associated with a spleen LP-like B-cell lymphoma. Clonal expression of both membrane and secreted µ chain isoforms was demonstrated at the mRNA level by high throughput sequencing. The Myd88L252P tumor transcriptomic signature identified both proliferation and canonical NF-κB p65/RelA activation. Comparison with MYD88L265P WM showed that Myd88L252P tumors also shared the typical lymphoplasmacytic transcriptomic signature of WM bone marrow purified tumor B-cells. Altogether these results demonstrate for the first time that continuous MYD88 activation is specifically associated with clonal transformation of differentiating IgM B-cells. Since MYD88L252P targets the IgM PC differentiation continuum, it provides an interesting preclinical model for development of new therapeutic approaches to both WM and aggressive MYD88 associated DLBCLs.

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“…Serum was obtained from blood collected retro-orbitally. Specific ELISA and serum electrophoresis assay were performed as previously described ( 19 , 22 ).…”

Section: Methodsmentioning

confidence: 99%

Continuous MYD88 Activation Is Associated With Expansion and Then Transformation of IgM Differentiating Plasma Cells

et al. 2021

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“…ROC curve analysis for treatment‐free survival (TFS) in hypogamma/CLL patients based on IgA level ( P = 0·004). 22,45‐48 …”

Section: Resultsmentioning

confidence: 99%

“…ROC curve analysis for treatment-free survival (TFS) in hypogamma/CLL patients based on IgA level (P = 0Á004). 22,[45][46][47][48]. [Colour figure can be viewed at wileyonlinelibrary.com] Kaplan-Meier treatment-free survival (TFS) and overall survival (OS) curves of IgG/CLL (A,B), hypogamma (C,D), and IgM/CLL (E,F)…”

mentioning

confidence: 99%

Monoclonal gammopathy and serum immunoglobulin levels as prognostic factors in chronic lymphocytic leukaemia

Corbingi

Innocenti

Tomasso³

et al. 2020

Br J Haematol

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Summary The relationship between chronic lymphocytic leukaemia (CLL) and qualitative/quantitative gammaglobulin abnormalities is well established. Nevertheless, in order to better understand this kind of connection, we examined 1505 patients with CLL and divided them into four subgroups on the basis of immunoglobulin (Ig) aberrations at diagnosis. A total of 73 (4·8%), 149 (10%), 200 (13·2%) and 1083 (72%) patients were identified with IgM monoclonal gammopathy (IgM/CLL), IgG monoclonal gammopathy (IgG/CLL), hypogammaglobulinaemia (hypo‐γ) and normal Ig levels (γ‐normal) respectively. IgM paraprotein was significantly associated with a more advanced Binet/Rai stage and del(17p)/TP53 mutation, while IgG abnormalities correlated with a higher occurrence of trisomy 12. Patients with any type of Ig abnormality had shorter treatment‐free survival (TFS) but no significant impact affecting overall survival (OS) compared to those with normal Ig levels.

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“… 5 , 6 , 7 Unmutated IGHV (UM‐CLL) genes are strongly associated with poor overall survival, while Binet stage A patients with mutated IGHV (M‐CLL) genes have a very good prognosis, especially when serum protein electrophoresis is normal. 5 , 6 , 8 Other prognostic cytogenetic markers include isolated del(13q), which is associated with good prognosis, del(11q), which is thought to correspond to ATM inactivation and trisomy 12, which defines a CLL group with an intermediate prognosis. 9 , 10 …”

Section: Introductionmentioning

confidence: 99%

“…Among the numerous other published prognosis factors, only IGHV mutational status and the presence of TP53 mutations or deletions, are consensually accepted as predictive for CLL progression and resistance to therapy, respectively 5‐7 . Unmutated IGHV (UM‐CLL) genes are strongly associated with poor overall survival, while Binet stage A patients with mutated IGHV (M‐CLL) genes have a very good prognosis, especially when serum protein electrophoresis is normal 5,6,8 . Other prognostic cytogenetic markers include isolated del(13q), which is associated with good prognosis, del(11q), which is thought to correspond to ATM inactivation and trisomy 12, which defines a CLL group with an intermediate prognosis 9,10 …”

Section: Introductionmentioning

confidence: 99%

A reduced panel of eight genes (ATM, SF3B1, NOTCH1, BIRC3, XPO1, MYD88, TNFAIP3, and TP53) as an estimator of the tumor mutational burden in chronic lymphocytic leukemia

Chauzeix

Pastoret

Donaty

et al. 2020

Int J Lab Hematology

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Introduction Mutational complexity or tumor mutational burden (TMB) influences the course of chronic lymphocytic leukemia (CLL). However, this information is not routinely used because TMB is usually obtained from whole genome or exome, or from large gene panel high‐throughput sequencing. Methods Here, we used the C‐Harrel concordance index to determine the minimum panel of genes for which mutations predict treatment‐free survival (TFS) as well as large resequencing panels. Results An eight gene estimator was defined encompassing ATM, SF3B1, NOTCH1, BIRC3, XPO1, MYD88, TNFAIP3, and TP53. TMB estimated from either a large panel of genes or the eight gene estimator was increased in treated patients or in those with a short TFS (<2 years), unmutated IGHV gene or with an unfavorable karyotype. Being an independent prognostic parameter, any mutation in the eight gene estimator predicted a shorter TFS better than Binet stage and IGHV mutational status among patients with an apparently non‐progressive disease (TFS >6 months). Strikingly, the eight gene estimator was also highly informative for patients with Binet stage A CLL or with a good prognosis karyotype. Conclusion These results suggest that the eight gene estimator, that is easily achievable by high‐throughput resequencing, brings robust and valuable information that predicts evolution of untreated patients at diagnosis better than any other parameter.

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Normal serum protein electrophoresis and mutated IGHV genes detect very slowly evolving chronic lymphocytic leukemia patients

Cited by 6 publications

References 37 publications

Continuous MYD88 Activation Is Associated With Expansion and Then Transformation of IgM Differentiating Plasma Cells

Continuous MYD88 Activation Is Associated With Expansion and Then Transformation of IgM Differentiating Plasma Cells

Monoclonal gammopathy and serum immunoglobulin levels as prognostic factors in chronic lymphocytic leukaemia

A reduced panel of eight genes (ATM, SF3B1, NOTCH1, BIRC3, XPO1, MYD88, TNFAIP3, and TP53) as an estimator of the tumor mutational burden in chronic lymphocytic leukemia

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