Comprehensive molecular dynamics of plasma cell differentiation in Waldenstr÷m macroglobulinemia
HIPP N. 1, GRASSEAU A. 1, LEONARD S. 1, NONN C. 1,2, PANGAULT C. 1,2, FEST T. 1,2, DECAUX O. 1,2, DELALOY C. 1
1 UMR INSERM S1236, Univ Rennes, EFS, LabEx IGO, Rennes, France; 2 CHU Rennes, P˘le Biologie, Rennes, France
Terminal differentiation of B lymphocytes into plasma cells (PCs) is finely controlled in time and space in response to signals from the microenvironment. The disruption of the signaling pathways that control this process is at the origin of lymphoproliferations and lymphomas. Waldenström macroglobulinemia (WM) is a specific entity of non-Hodgkin's lymphoma with bone marrow involvement of clonal immunoglobulin(Ig)M-secreting plasmacytoid lymphocytes. It is postulated that malignant WM clones originate from B cells arrested after somatic hypermutation in the germinal center before differentiation to PCs. A striking aspect of WM is the intratumor cell fate heterogeneity, ranging from mature B cells to PCs, suggesting an ongoing PC differentiation. Yet, the exact molecular pathways driving malignant B-cell development are currently unknown. Here, we found that WM patients' B cells can successfully differentiate into antibody-secreting cells in a controlled culture system that mimics antigen priming in the context of PAMPs and T cell help. In line with their low expression of BACH2, WM B cells more rapidly express the PC program and differentiate to IgM PCs as compared with normal B cells. To better understand PC differentiation and the molecular dynamics responsible for tumor cell fate plasticity, we used single-cell RNAseq with VDJ sequencing of malignant cells isolated from blood, bone marrow and along time in our culture system. Two differentiation trajectories exist for tumor cells, one leading to antibody-secreting cells, while the persistent WM B cell population expresses a memory signature. Pseudotime analysis revealed the altered transcriptional dynamics responsible for abnormal PCs. At least, we showed that BACH2 enforced repression in normal B cells drives PC differentiation that mimics WM PCs. Altogether, these results improve our understanding of the transcription factor network that governs WM cell fate plasticity and open new therapeutic options.