TCL1A expression delineates biological and clinical variability in B-cell lymphoma

Abstract

The assembly of a collection of gene-expression signatures of the major types of B-cell non-Hodgkin's lymphoma has identified increased T-cell leukemia/lymphoma 1A (TCL1) expression in multiple lymphoma types and cases, and has enabled the investigation of the functional and clinical importance of TCL1 expression. Specifically, Burkitt's lymphoma cases show a homogeneously strong expression of TCL1, whereas diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, nodal marginal zone lymphoma, and splenic marginal zone lymphoma display a striking variability in the intensity of TCL1 staining. This was validated in two independent series. A Gene-Set Enrichment Analysis of the genes correlated with TCL1A expression found that variation in the level of expression of TCL1A was significantly associated with some of the most important gene signatures recognizing B-cell lymphoma pathogenesis and heterogeneity, such as germinal center, B-cell receptor, NF-jB (and its target genes), death, MAP kinases, TNFR1, TOLL, and IL1R. Additionally, TCL1 expression was correlated with shorter time to treatment in chronic lymphocytic leukemia cases and shorter lymphoma-specific survival in mantle cell lymphoma series, thus indicating the clinical and biological significance of TCL1 expression, and suggesting TCL1A as a potential therapeutic target.

Nutlin-3 Downregulates the Expression of the Oncogene TCL1 in Primary B Chronic Lymphocytic Leukemic Cells

“…It has been previously described that TCL1 shows a differential and regulated expression pattern in B-CLL (5). Different groups of investigators have observed association of high protein levels of TCL1 with features of aggressive disease in B-CLL (6,7). These results indicate that deregulation of TCL1 is critically important in the pathogenesis of the aggressive form of B-CLL (3).…”

High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia

“…24,25 We have previously described that TCL1 shows a differential and regulated expression pattern in CLL, 20 and an association of high protein levels of TCL1 with features of aggressive disease in CLL has been subsequently indicated by us and others. 20,26,27 We show here that the growth stimulatory effects of BCR engagement in CLL cultures are strongly correlated with the levels of TCL1 and the kinetics of TCL1-AKT recruitment to BCR membrane complexes. Increased TCL1 levels are also strongly associated with inferior clinical outcome, independent of treatment.…”

New developments in the pathology of malignant lymphoma. A review of the literature published from August 2013 to December 2013

“…None of the studies were confirmatory in nature, and those are the only ones in which clinical application can be found. Schreck et al [75] demonstrate that a large number of Th2 cells in HL is related to better survival; Dong et al [76] show that bcl10 expression (next to t (11;14)) is related to HP-eradication unresponsiveness; according to Wang et al [77], cytoplasmic sox11-expressing MCLs have a poorer survival; mutation nor polymorphism of the CD20 gene is predicting rituximab response (Sar et al [78]); Aktas et al [79] show that high apoptotic index is related to good prognosis in pediatric lymphomas; Lenz et al [80] describes new gene signatures that predict therapy response in DLBL; Peh et al [81] found that bcl-6 expression is associated with poor survival in DLBL and immunohistochemically determined ABC not; according to Johnson et al [82], DLBL with low CD20 expression have lower survival rate; Ki67 and Pim1 are independent indicators of poor survival in MCL (Hsi et al [83]); low Ki67 is a negative predictor of survival in DLBL (Hasselblom et al [84]); SIRT1 expression is associated with poor prognosis in DLBL (Jang et al [85]); in FL, Johnson et al [86] show that secondary genetic alterations indicate aggressive behavior; Hasselblom et al [87] show that the number of CD68-positive cells in DLBL does not predict prognosis; TCL1A is associated with more aggressive clinical behavior in CLL and MCL according to Aggarwal et al [88]; aberrations in the MYC locus are associated with poor outcome in DLBL (Klapper et al [89] and Yoon et al [90]); expression of P-glycoprotein indicates therapy unresponsiveness in nasal type NK/T cell lymphoma according to Wang et al [91];…”