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

Kristin Schmidt,Oliver Popp,Robin Graf,Philipp Mertins,Klaus Rajewsky,Thomas Sommermann,Christine Kocks,Ulrike Sack,Wiebke Winkler

doi:10.3389/fimmu.2020.602868

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.

Highlights

Waldenström’s macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma, characterized by bone marrow (BM) infiltration of small, IgM-positive lymphocytes with varying degrees of plasmacytoid or plasma cell differentiation and the presence of monoclonal immunoglobulin M (IgM) paraproteins (M-spikes) in the serum [1,2,3,4,5]
First described in activated B-cell (ABC)-like subtype of diffuse large B-cell lymphoma (DLBCL) [where it occurs in 21% of patients [15]], the MYD88L265P mutation constitutively activates NF-kB and JAK kinase signaling through TLR9, IRAK1 and IRAK4 [16, 17], and independently through BTK [18], conferring a pro-survival advantage to mutated B cells
Our results suggest that the Myd88L252P mutation causes elevated serum IgM levels and confers a subtle survival or growth advantage on IgM-expressing B cells that encompass a spectrum of differentiation states, including GC B cells and plasma cells

Summary

Introduction

Waldenström’s macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma, characterized by bone marrow (BM) infiltration of small, IgM-positive lymphocytes with varying degrees of plasmacytoid or plasma cell differentiation and the presence of monoclonal immunoglobulin M (IgM) paraproteins (M-spikes) in the serum [1,2,3,4,5]. First described in activated B-cell (ABC)-like subtype of diffuse large B-cell lymphoma (DLBCL) [where it occurs in 21% of patients [15]], the MYD88L265P mutation constitutively activates NF-kB and JAK kinase signaling through TLR9, IRAK1 and IRAK4 [16, 17], and independently through BTK [18], conferring a pro-survival advantage to mutated B cells In line with these findings, an earlier attempt to model the Myd88L265P mutation in mice in vivo produced fulminant B lymphoproliferative disease and occasional ABC-DLBCL-type lymphoma [19], while a more recent study reported low-grade lymphoproliferative disease with certain pathological features of WM [20]. In both mouse models the observed lymphoproliferation was polyclonal

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Results

Conclusion