Biological pathways in B-cell non-Hodgkin s Lymphoma

University dissertation from Stockholm : Karolinska Institutet, Department of Medicine at Huddinge University Hospital

Abstract: Non-Hodgkin s lymphomas have become more prevalent in the past 20 years. They constitute a diverse group of lymphoid tumors that have been understood and classified according to their clinical behaviour, anatomic location, morphology, immunophenotype, cytogenetics, and gene expression profile. Microarray profiling yields information about large number of genes, which can be involved in different functional pathways of importance for the biology of lymphomas. In this thesis, we started to look at major types of B-cell lymphomas by using the microarrays, with the aim to have a macroscopic view of the signaling pathways involved in their biology. Functional signatures such as cellcycle, apoptosis, cytokine-cytokine receptor interaction, T-cell receptor, B-cell receptor (BCR), cell adhesion, and NF-kappaB activation describe multiple dysregulated pathways in lymphomas. The BCR gene expression delineates distinct functional heterogeneity within each lymphoma. In CLL, the BCR genes were positively correlated to the expression of the pathways for CREB, MAPK/ERK5, BCR Signaling and MET. In MCL, the BCR genes were additionally coregulated to GC T-helper cell, integrins, CXCR4 and blood pan-B cell genes. In FL, BCR genes showed positive correlation to the mTOR-, GC B-cell-, Akt- and BCR Signaling-, blood pan B-cell- and ERK5- pathways while in DLBCL they were co-expressed with GC-B-cell, blood pan-B cell and c-myc targets. Interestingly, targets for BLIMP-1, an important transcription factor, were positively correlated to the expression of BCR genes in all the four mentioned lymphomas (Paper I). During unsupervised clustering, we observed that BCR genes and TCL1 oncogene were expressed in the same cluster. Variation in the level of gene array expression of TCL1A was significantly associated with gene signatures recognizing B-cell lymphoma biology, such as germinal center, BCR, NF-êB (and its target genes), death, MAP kinases, TNFR1, TOLL, and IL1R. High expression of TCL1 was related to poor prognosis in CLL and MCL in microarray and immunohistochemistry respectively. (Paper II). Thus, we found in these studies (Paper I and II) that BCR and TCL1 are important to lymphoma biology, while they also define striking heterogeneity within known lymphoma types. The role of somatic hypermutation(SHM) of the B-cell receptor in the lymphoma biology was demonstrated (paperIII); we identified here surrogate markers or genes in the cell machinery that accompany the process. Markers of SHM (such as RAD51C and CDK7) and ongoing SHM (TFDP1 and POLA) are some of the genes involved in DNA repair and replication. CDK7 and RCC1, separately and together, showed prognostic value in Mantle Cell Lymphoma on immunohistochemistry (Paper III). In the end, we narrowed our attention to Follicular Lymphoma (FL) and the microenvironment. Using a uniqueapproach of flow cytometry and automated microscopy scoring in FL, we identified that the clinical outcome was independently predicted by different immune cells: CD4+ T-cells and macrophages were associated with poorprognosis while cytotoxic T-lymphocytes and T-regulatory cells were associated with better prognosis (Paper IV). The results presented in the thesis provide insight and understanding of lymphoma biology that would facilitate discovery of markers of prognostic and hopefully therapeutic importance.

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