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TCL1A Expression Delineates Biological and Clinical Variability in B-Cell Lymphoma

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TCL1A Expression Delineates Biological and Clinical Variability in B-Cell Lymphoma Modern Pathology (2009) 22, 206–215 & 2009 USCAP, Inc All rights reserved 0893-3952/09 $32.00 www.modernpathology.org TCL1A expression delineates biological and clinical variability in B-cell lymphoma Mohit Aggarwal1,4, Raquel Villuendas1, Gonzalo Gomez2, Socorro M Rodriguez-Pinilla1, Margarita Sanchez-Beato1, David Alvarez1, Nerea Martinez1, Antonia Rodriguez1, Maria E Castillo1, Francisca I Camacho1, Santiago Montes-Moreno1, Jose A Garcia-Marco3, Eva Kimby4, David G Pisano2 and Miguel A Piris1 1Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; 2Bioinformatics Unit, Structural Biology and Biocomputing Programme, CNIO, Madrid, Spain; 3Department of Haematology, Hospital Universitario Puerta de Hierro, Madrid, Spain and 4Division of Hematology, Department of Internal Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden 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. Modern Pathology (2009) 22, 206–215; doi:10.1038/modpathol.2008.148; published online 26 September 2008 Keywords: TCL1; B-cell lymphoma; gene expression; clinical variability Molecular pathogenesis of non-Hodgkin’s lymphoma molecular markers, and to apply our accumulated is determined by an interaction between the tumor knowledge about lymphoma pathogenesis to targeted cell and its microenvironment.1 This interaction therapy. Although the effort expended on recognizing controls the activation of B-cell receptor, NF-kB, and disease-specific molecular markers has led to the other signaling pathways, and eventually regulates identification of many individual markers, such as apoptosis and cell cycle.2,3 Some primary and CCND1, BCL6, ZAP70, and CD30, the molecular secondary cytogenetic alterations have been identi- pathogenesis of the different types of non-Hodgkin’s fied that involve oncogenes such as c-MYC lymphoma seems to be characterized by the activation in Burkitt’s lymphoma, BCL-2 translocation (t14;18) of some major B-cell lymphoma pathways that are in follicular lymphoma, CCND1 translocation (t11;14) commonly deregulated in B-cell non-Hodgkin’s lymp- in mantle cell lymphoma, TCL1A deregulation in homa types. To date, however, little has been done to chronic lymphocytic leukemia,4 and BCL-6 deregu- identify nonlymphoma-type-specific alterations that lation in diffuse large B-cell lymphoma.5,6 However, could consistently determine lymphoma pathogenesis. there is an urgent need to identify additional accurate Here we have focused on the biological and clinical relevance of TCL1A expression, and its relation with B-cell receptor activation. The involve- Correspondence: Dr MA Piris, MD, PhD, Centro Nacional de ment of B-cell receptor signaling7 and the TCL1A Investigaciones Oncologicas, C/Melchor Fernandez Almagro no 3, oncogene8 in pathogenesis of B-cell non-Hodgkin’s Madrid E-28029, Spain. E-mail: [email protected] lymphoma has already been demonstrated. Dys- Received 18 July 2008; revised and accepted 14 August 2008; regulation of TCL1A expression in T cells, by published online 26 September 2008 chromosome rearrangements, or in B cells, possibly TCL1A expression in B-cell lymphoma M Aggarwal et al 207 by Epstein–Barr virus infection or microRNA target- Table 1 Main clinical findings from (a) CLL (98 patients) and (b) ing, enhances cell proliferation and survival, and MCL (64 patients) leads to cell transformation following prolonged Clinical variables Total latency.4,9–11 Dysregulation of TCL1A, secondary to miR-29 and miR-181 loss, is a causal event in the (a) CLL pathogenesis of the aggressive form of chronic Sex lymphocytic leukemia, and probably of splenic Male 60 marginal zone lymphoma.9,12 Aberrant TCL1A Female 38 expression also promotes malignant transformation a 13 Age at diagnosis (year) of germinal center B cells. A role of TCL1A o60 34 oncogene in the pathogenesis of other B-cell non- 60–69 30 Hodgkin’s lymphoma malignancies has already X70 32 been proposed,4 but the exact mechanisms by RAI stage which TCL1A regulates tumor development in 052 non-Hodgkin’s lymphoma is not yet fully under- 4046 stood.14 Here we analyze gene-expression profiling data obtained from the analysis of the various B-cell Binet stage lymphoma types, to investigate the functional A76 B+C 22 significance of TCL1A in B-cell non-Hodgkin’s lymphoma and the clinical relevance of increased CD38 expressiona TCL1A expression in mantle cell lymphoma and o20% 65 chronic lymphocytic leukemia. X20% 23 First-line treatment (at 60 months of follow-up) Yes 43 Materials and methods No 55 Patients and Controls (b) MCL Sex The microarray data (GSE9327) from 187 cases of Male 45 B-cell non-Hodgkin’s lymphoma available in the Female 19 GEO public repository under MIAME regulations (http://www. ncbi.nlm.nih.gov/geo/query/acc.cgi? Agea o60 years 21 token ¼ ftenzyyykicqqfi&acc ¼ GSE9327) were used X60 years 30 in this study. The microarray data have been previously published by our group and include Stagesa those for Burkitt’s lymphoma (9 cases), diffuse large I0 B-cell lymphoma (36 cases),15 mantle cell lymp- II 4 16 III 7 homa (38 cases), chronic lymphocytic leukemia IV 48 (38 cases),17 follicular lymphoma (33 cases),18 nodal marginal zone lymphoma (6), and splenic marginal Extranodal involvementa zone lymphoma (27 cases).19 Reactive lymph nodes o239 X from eight patients and spleen from three patients 225 were also analyzed. The cases were selected on the Serum LDHa basis of the standard WHO Classification crite- pNormal 38 ria.20,21 All samples were fresh frozen diagnostic 4Normal 12 samples taken previous to treatment, and were ECOG performance statusa provided by the hospitals and the CNIO Tumor o242 Bank, under the supervision of the Local Ethic X211 Committees. In addition, an already published series of 98 International prognostic indexa Low/low-intermediate 27 cases of chronic lymphocytic leukemia hybridized High/high-intermediate 25 on a chronic lymphocytic leukemia-specific 1.9K Oligonucleotide Microarray (Agilent Technology) Overall survival (at 60 months) was used for TCL1A analysis.22 Main clinical Alive 36 characteristics of the patients22 are summarized in Dead 28 Table 1a. CLL, chronic lymphocytic leukemia; ECOG, Eastern Cooperative Additional 64 patients diagnosed as mantle cell Oncology Group; LDH, lactate dehydrogenase; MCL, mantle cell lymphoma23 were collected by the CNIO Tumor lymphoma. Bank Network under the supervision of the Local aData are not available for all the cases. Ethic Committees. All cases were histologically reviewed by a team of pathologists (SMRP and MAP), in accordance with the WHO criteria.20,21 Modern Pathology (2009) 22, 206–215 TCL1A expression in B-cell lymphoma M Aggarwal et al 208 Figure 1 TCL1 gene expression in B-cell non-Hodgkin’s lympho- ma types: using cases hybridized on OncoChip. The expression for the cases was normalized with respect to the expression of reactive lymph nodes, whereas gene expression for splenic marginal zone lymphoma was normalized against normal spleen. 23 These samples were used to do a tissue microarray Figure 2 Oncomine analysis of TCL1A in non-Hodgkin’s lym- (see below). Tumoral diagnostic samples were phoma: (a) Differential expression of TCL1A in lymphoma types: obtained from untreated patients. Patient records Burkitt’s lymphoma (HIV þ ), diffuse large B-cell lymphoma and clinical data were reviewed retrospectively. The (centroblastic), diffuse large B-cell lymphoma (immunoblastic), diffuse large B-cell lymphoma, hairy-cell Leukemia, Burkitt’s patient data for analyzable cases are summarized in lymphoma, follicular lymphoma, B-cells, mantle cell lymphoma, Table 1b. and chronic lymphocytic leukemia, respectively (www.oncomi ne.org). Data link source: http://www.ncbi.nlm.nih.gov/projects/ geo/query/acc.cgi?acc ¼ GSE2350.26 (b) TCL1A expression in diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. Data link sources: http://llmpp.nih.gov/ Gene-Set Enrichment Analysis and Regulatory lymphoma/analysis.shtml, http://www.ncbi.nlm.nih.gov/geo/ Network Analysis query/acc.cgi?acc ¼ GSE60.35 We conducted Gene-Set Enrichment Analysis to understand the functional pathways that are cor- Tissue Microarray and Immunohistochemistry
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