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

Abstract

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.

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

“…( 15 ), and, being in line with those of K Schmidt et al. ( 16 ), firmly demonstrate the specific transforming effect of MYD88 activation in IgM PC differentiating B-cells.…”

“…This signature differentiates MYD88 L265P WM from other indolent B-cell tumors including marginal zone lymphomas. Our results contradict the conclusions of Sewastianik et al (15), and, being in line with those of K Schmidt et al (16), firmly demonstrate the specific transforming effect of MYD88 activation in IgM PC differentiating B-cells.…”

“…In that view, K Schmidt et al recently published a mouse model with a transgene closed to the one of the Knittel's model. But, after exploring the effect of MYD88 activation in three different Cre context, Cd19-Cre, Cg1-Cre and Cd19-Cre ERT2 , as well as analyzing the effect of NP-immunization, the authors concluded that MYD88 continuous activation promotes survival of long term IgM expressing B-cells with clonal restriction a monoclonal serum IgM paraprotein resulting in an IgM MGUS-like disorder (16).…”

“…Recently, K Schmidt et al. reported a mouse model in which MYD88 activation was responsible for an indolent lymphoproliferative disorder resembling to IgM monoclonal gammopathy of unknown significance (IgM MGUS), the asymptomatic preclinical stage of WM ( 16 ).…”

“…Therefore, the question of a direct role for MYD88 in the development of a lymphoplasmacytic lymphoma with monoclonal IgM secretion is still open. Recently, K Schmidt et al reported a mouse model in which MYD88 activation was responsible for an indolent lymphoproliferative disorder resembling to IgM monoclonal gammopathy of unknown significance (IgM MGUS), the asymptomatic preclinical stage of WM (16).…”