We show that these mice first developed early expansion of CD93neg IgM PCs with an increase in both IgM secretion and bone marrow relocalization of IgM B-cells. 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 NVP-CGM097 of both membrane and secreted chain isoforms was demonstrated at the mRNA level by high throughput sequencing. The Myd88L252P tumor transcriptomic signature identified both proliferation and canonical NF-B p65/RelA activation. Comparison with 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. Keywords: MYD88 L265P mutation, lymphoplasmacytic lymphoma/Waldenstroms macroglobulinemia, IgM secretion, monoclonal Ig peak, B-cell lymphoma, plasma cell Introduction Waldenstr?ms macroglobulinemia (WM) is an incurable indolent B-cell lymphoma of the elderly accounting for less than 5% of B-cell lymphomas with, as unique characteristics, a serum IgM peak and primary medullary localization of lymphoplasmacytic cells that exhibit continuous differentiation from mature B lymphocytes to IgM secretory plasma cells (1). Secondary lymphoid organ infiltration and/or a leukemic phase is found in 20% cases. Other manifestations include neuropathy, cryoglobulinemia, skin rash, cold-agglutinin hemolytic anemia, and amyloidosis (2). The discovery of the activating mutation of (being the far most frequent) in more than 90% of WM cases contributed NVP-CGM097 to the concept that this entity is genetically distinct from other B-cell lymphomas (3, 4). Being present in 50% of IgM monoclonal gammopathies of undetermined significance (MGUS), NVP-CGM097 mutations are most likely a primary event in WM (5). Considered as secondary genetic events, activating mutations of (CXCR4S338X or CXCR4WHIM), a receptor implicated in migration and bone marrow (BM) homing of leucocytes, are found in 30% of WM cases (6). Additional mutations of or have been reported (7). Despite these advances, WM pathophysiology is incompletely understood. Its treatment remains challenging and the exact role of mutations in the emergence NVP-CGM097 of lymphoplasmacytic B-cell clones is not known (7, 8). Indeed, mutations are also found in 30% of activated B-cell type diffuse large B-cell lymphomas (ABC-DLBCL), more than half of primary cutaneous DLBCLs, leg type, and many DLBCLs at immune-privileged sites but not in plasma cell myelomas, even IgM types (9). NVP-CGM097 It should be noted that IgM expression is a surrogate marker of ABC-DLBCLs (10). Moreover, all these aggressive B-cell tumors associated with MYD88, which often exhibit morphological features of plasma cell (PC) differentiation, are all associated with expression of TNFRSF10B the PC differentiation marker IRF4. MYD88 protein is the canonical adapter for inflammatory signaling pathways to downstream members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families. Forming the myddosome complex, MYD88 binds IL-1R or TLR family members to IRAK kinases family. IRAK activation leads to activation of the NF kappa B (NF-B) transcription factor and interferon 3 and 7 regulatory factors (IRF3 and 7). MYD88L265P constitutively increases.