Flow cytometry detection of CD138 expression continuum between monotypic B and plasma cells is associated with both high IgM peak levels and MYD88 mutation and contributes to diagnosis of Waldenström macroglobulinemia

Abstract

Background: Differential diagnosis of Waldenström macroglobulinemia (WM) with other indolent B-cell malignancies is still a challenge. Here, we propose an original and simple analysis of routine flow cytometry (FCM) unraveling the characteristic ongoing plasma cell (PC) differentiation of WM tumor B-cells.Methods: FCM analysis of both B-cells and PC was performed on a series of 77 patients with IgM peak. MYD88 and CXCR4 mutations were studied using an allele-specific PCR and by high throughput sequencing.Results: Twenty seven (35%), 46 (58%) and 4 (5%) patients were classified as WM, IgM monoclonal gammopathy of undetermined significance (MGUS) or other B-NHL respectively. MYD88 mutation was found in 25/27 WM (93%) and in 29/46 MGUS (63%). Using FCM, monotypic B-cells were found in 27/27 WM (100%) and 34/46 MGUS (74%). Monotypic CD138pos/CD38pos PCs were detected in 23/27 WM (85%) and 25/46 MGUS (54%). Highlighting the ongoing PC differentiation of WM tumor B-cells by FCM, we evidenced a CD138 expression continuum between monotypic B-cells and PCs. This pattern remained absent in control samples and was significantly associated with higher IgM peaks (p = 6.10 −5 ) and MYD88 mutations (p = 10 −3 ) in both WM and MGUS cases.Conclusions: FCM exploration of both B-cells and PC led to identify a CD138 expression continuum as an objective marker of ongoing PC differentiation of WM tumor cells and was strongly associated with increased IgM peak levels and MYD88 mutations.

Single‐cell resolution of plasma cell fate programming in health and disease

“…The most striking aspect is the intratumor cell fate heterogeneity, ranging from mature B cells to PCs, suggesting an ongoing PC differentiation from clonal B cells believed to be memory like cells with PC differentiation ability [123]. In line with this, recent flow cytometry analysis revealed a continuum of the PC marker CD138 expression between the malignant B‐cell subset and the more differentiated subset infiltrating the BM [124]. Part of these differentiated WM tumor cells, the plasmacytoid lymphocytes, co‐expressed the pan‐B‐cell markers CD19 and CD20.…”

Broadening the horizon: potential applications of CAR-T cells beyond current indications

“…have recently highlighted the role of CXCR4 in WM and its possible use as a therapeutic target ( 377 ). Additionally, CD138 has recently emerged as a potentially identifying feature of WM tumor cells, associated with IgM peaks and MYD88 mutations ( 378 ). Recent research has shown the role of nanoscale organization of CARs and TCRs for CAR-T cells targeting CD138 with yet unknown consequences ( 379 ).…”

B-cell specific expression of the murineMyd88L252Pmutation correlates with the establishment of an immunosuppressive microenvironnement in Waldenström macroglobulinemia lymphoplasmacytic lymphoma

“…Being specific of WM, clonal cells exhibit a continuous differentiation between the small mature lymphocyte and the mature plasma cell (PC). We recently demonstrated that this unique characteristic may be used as a biological marker for WM diagnosis by evidencing the B-cell clonality in both lymphocytes and plasma cell by flow cytometry [1]. Similar to other lymphomas, cytogenetic and molecular abnormalities have been identified and can be used as prognostic factors.…”