In vitro modelling and analysis of the B cell malignancy Waldenstrom macroglobulinemia

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, which leads to an array of clinical
symptoms. WM is also characterised by MYD88L265P mutation in ~90% of
patients which aberrantly activates NF-ĸB. MYD88L265P is not unique to WM,
and a better understanding of how MYD88L265P disrupts normal plasma cell
differentiation is key to understanding this disease.
To address this, the effects of MYD88L265P were tested in human B cells
under conditions promoting PC differentiation. Naïve and memory B cells
overexpressing MYD88L265P displayed no survival or proliferation advantage
and differentiated as normal. Previous studies have indicated that the antiapoptotic protein BCL2 enhances lymphomagenesis and is expressed at
high levels in WM cells. To determine whether BCL2 activity would
potentiate the effects of MYD88L265P, combined expression was evaluated. B
cells overexpressing MYD88L265P and BCL2 differentiate and proliferate
slower but survive for longer than controls.
Memory B cells produce a smaller proportion of plasma cells and don’t
transition to an IgG-dominated population of cells. Naïve B cells also don’t
transition to an IgG-dominated population but additionally show a failure to
produce CD27+CD38+CD138- plasmablasts or CD38+CD138+ plasma cells.
This study confirms previously reported claims that MYD88L265P alone is
insufficient to induce malignant transformation. The co-expression of MYD88
and BCL2 alters differentiation, proliferation and survival of healthy human B
cells, providing a framework for mechanistic studies of WM-associated
aberrant gene function in human cells