Abstract

The kinase comodulator TCL1 is the primary initiating oncogene in T-cell prolymphocytic leukemia and can produce B-cell or T-cell chronic lymphocytic leukemia (CLL) following transgenic expression in mice. Given its strong expression in some non-neoplastic B-cell subsets, the role of TCL1 as an oncogene in human B-cell tumors is less clear. Using a recently developed TCL1 monoclonal antibody (clone 1–21), we examined the relationship between TCL1 expression and B-cell maturation stage in tumor tissue arrays, lymphoma cell lines, primary tumor samples and in vitro stimulation assays. Results were compared with immunohistochemical expression of a variety of maturation, activation and cell proliferation markers and with the somatic hypermutation status determined by VH transcript analysis (<2% sequence divergence in VH regarded as “pre-germinal center”). In non-neoplastic B-cells, TCL1 was strongly and uniformly expressed in naive B-cell subsets, but was variably expressed in subsets of germinal center B-cells, with complete absence of expression in immunoblasts and plasma cells. In germinal center B-cells, TCL1 was expressed more strongly in the quiescent centrocyte fraction than in the proliferating centroblasts. This pattern was replicated in human B-cell lymphoma lines and tumors with complete absence of TCL1 in myeloma cases (n = 35) and monocytoid B-cells in marginal zone lymphoma (n = 8) and dim or absent expression in the majority of the mutated/post-germinal center subset of B-CLL (10/15, 67%). In contrast, TCL1 showed strong but modulated expression in the majority of unmutated/pre-germinal center type of B-CLL (14/19, 74%), and mantle cell lymphoma (MCL, 44/57, 84%), and less frequently in follicular lymphoma (FL, 21/47, 45%). In B-CLL, TCL1 was overexpressed in non-proliferating cells within the pseudo-follicular proliferation centers but was markedly downregulated in the CD23+bright PCNA+ proliferating tumor cell component. Similarly in MCL, TCL1 was downregulated in the proliferative component but upregulated in tumor cells in follicular and mantle zone locations versus the diffuse areas. In FL, the highest levels of TCL1 expression were found in those cases that most strongly expressed the germinal center markers CD10 and bcl-6, but TCL1 staining was inversely correlated with expression of proliferation and activation markers, such as CD23. In 3 FL cases with multiple biopsies at different tissue sites, TCL1 was downregulated in tumor cells at extranodal sites as compared to those within lymph node follicles. Thus, the dynamic regulation of TCL1 in B-cells and derived tumors is likely due to changes in the balance between stimulatory microenvironmental influences within the lymphoid follicle and inhibitory signals during cell cycle progression/proliferation. In post-germinal center tumors, TCL1 expression is effectively silenced, and no longer exhibits this dynamic regulation pattern. These studies strongly suggest that TCL1 exerts its effects in promoting cell survival in quiescent B-cell subsets prior to and in the absence of an (antigenic) proliferative signal.

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