Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells

Abstract

MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.

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

“…However, different from earlier studies, continuous activation of an endogenous Myd88 L252P mutation by CD19-Cre in our mouse cohort did not cause fulminant lymphoproliferative disease (19) or an increased transformation to B lymphoma or increased mortality (Table 1; Supplementary Figure 3A) (19,20). Rather than owing to differences in the human and mouse Myd88 proteins, as proposed recently by Sewastianik et al (20), these discrepancies may be caused by different external cues (such as TLR signaling induced by different microbial or mouse housing environments) (19) or the molecular effects of strong transgene overexpression (20), or both.…”

“…Our study is in line with the prevailing view that the development of WM requires additional mutations besides MYD88 L265P (19,20,36,(39)(40)(41)55). The observed B cell phenotypes are consistent with earlier work that assessed the effect of retroviral overexpression of mouse Myd88 L252P in B cells ex vivo (55) or B-cell-specific transgenic overexpression of human MYD88 L265P in vivo (20).…”

“…The need to remove negative feedback loops may explain the frequent occurrence of mutations that affect negative regulators of NF-kB in human WM or ABC-DLBCL patients (36,37,(72)(73)(74)(75). Our results (in genetic scenarios one and two) are also in line with the observation that human MYD88 L265P promotes in the mouse the development of a polyclonal, low-grade B cell lymphoproliferative disorder of lymphoplasmacytic appearance with increased serum IgM (20). However, different from earlier studies, continuous activation of an endogenous Myd88 L252P mutation by CD19-Cre in our mouse cohort did not cause fulminant lymphoproliferative disease (19) or an increased transformation to B lymphoma or increased mortality (Table 1; Supplementary Figure 3A) (19,20).…”

“…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 MYD88 L265P 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 Myd88 L265P 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). However, in both mouse models the observed lymphoproliferation was polyclonal.…”

Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B‐cell lymphoma

“…These findings confirmed the experimental data showing that MYD88 L265P alone is insufficient to drive malignant transformation in B cells and may cooperatively induce lymphoma with other genetic events. 46 Genetically defined-MCD subtype was closely related to multiple ENI, in particular with breasts and bones. These observations suggest a potential link of MCD genotype and immune evasion.…”