Gene Expression Profiling Reveals Aberrant T-cell Marker Expression on Tumor Cells of Waldenström's Macroglobulinemia

Purpose: That the malignant clone of Waldenström's macroglobulinemia (WM) demonstrates significant intraclonal heterogeneity with respect to plasmacytoid differentiation indicates the mechanistic complexity of tumorigenesis and progression. Identification of WM genes by comparing different stages of B cells may provide novel druggable targets. Experimental Design: The gene expression signatures of CD19⁺ B cells (BC) and CD138⁺ plasma cells (PC) from 19 patients with WM were compared to those of BC from peripheral blood and tonsil and to those of PC from the marrow of healthy (N-PC) and multiple myeloma donors (MM-PC), as well as tonsil (T-PC). The flow cytometry and immunofluorescence were used to examine T-cell marker expression on WM tumor cells. Results: Consistent with defective differentiation, both BC and PC from WM cases expressed abnormal differentiation markers. Sets of 55 and 46 genes were differentially expressed in WM-BC and WM-PC, respectively; and 40 genes uniquely dysregulated in WM samples were identified. Dysregulated genes included cytokines, growth factor receptors, and oncogenes not previously implicated in WM or other plasma cell dyscrasias. Interestingly, strong upregulation of both IL6 and IL6R was confirmed. Supervised cluster analysis of PC revealed that marrow-derived WM-PC was either MM-PC-like or T-PC-like, but not N-PC-like. The aberrant expression of T cell markers was confirmed at the protein level in WM-BC. Conclusions: We showed that comparative microarray profiles allowed to gain more comprehensive insights into the biology of WM. The data presented here have implications for the development of novel therapies, such as targeting aberrant T-cell markers in WM.

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