Enforcing MyD88^L265P expression in human plasma cell differentiation provides a tractable model for Waldenström’s Macroglobulinemia

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B807
Abstract ID: 4141

Presenting Author:
Adam Mabbutt , PhD Student at Univ. of Leeds

Abstract:

Waldenström’s Macroglobulinemia (WM) is a rare B cell neoplasm also classified as a ‘lymphoplasmacytic lymphoma’ where neoplastic cells have features of both B lymphocytes and plasma cells (PC). WM PCs secrete large amounts of IgM paraprotein. WM is also characterised by MyD88^L265P mutation in ~90% of patients which aberrantly activates NF-kB. MyD88^L265P is not unique to WM, and a better understanding of how MyD88^L265P disrupts normal plasma cell differentiation is key to understanding this disease.

To address this, the effects of MyD88^L265P were tested in human B-cells under conditions promoting PC differentiation. Primary human memory B cells transduced to overexpress MyD88^L265P retained the ability to generate a population expressing the PC marker CD138 during in vitro PC differentiation, but also generated proportionally more undifferentiated CD19⁺CD20⁺CD138^- cells than controls. MYD88^L265P-expressing cells had improved survival over a 13-day time-course when cultured using suboptimal cytokine concentrations. Under these conditions the MYD88^L265P—expressing cells generated an increased proportion of CD138⁺ cells relative to controls. Distinctively, these cells co-expressed the B cell marker CD20 and high levels of CD27, suggestive of a lymphoplasmacytic cell state. Thus, enforced expression of MYD88^L265P in primary human B-cells under conditions permissive for PC differentiation provides an experimental system to model WM biology in vitro.