Origin of Waldenstrom's macroglobulinaemia

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• Waldenstrom's macroglobulinaemia (WM) is a lymphoplasmacytic lymphoma characterized by MYD88^L265P mutation and monoclonal immunoglobulin M (IgM) secretion.
• WM cells typically exhibit a distinct immunophenotype (CD19⁺/CD22^low+/CD23^-/CD25⁺/CD27⁺/CD45⁺/CD38^low+/SmIgM⁺) and are usually unable to undergo class switch recombination.
• This immunophenotype shares similarities with human B memory cells, which constitute approximately 30% of peripheral B cells.

Purpose of the Study:

• To investigate the cellular origin of Waldenstrom's macroglobulinaemia.
• To compare the immunophenotype and genetic characteristics of WM cells with normal B cell subsets.

Main Methods:

• Immunophenotypic analysis of WM cells and normal B cells using flow cytometry.
• Analysis of IGHV mutation status and class switch recombination capacity in WM cells.
• Assessment of MYD88 mutation status in WM cases.

Main Results:

• The typical WM immunophenotype closely matches that of B memory cells, with 50% of WM cells being IgM⁺ and having undergone somatic hypermutation.
• WM cells demonstrate a capacity to differentiate into plasma cells, retaining their clonal identity.
• A subset of WM cases showed variations, including CD27^- cells, wild-type MYD88, absence of somatic hypermutation, or capacity for class switch recombination.

Conclusions:

• The majority of Waldenstrom's macroglobulinaemia cases likely originate from a B memory cell precursor.
• While B memory cell origin is predominant, a small fraction of WM cases may arise from different cellular origins, suggesting heterogeneity in WM pathogenesis.