Transcriptional Analysis of Mantle Cell Lymphoma a Global Search for Cellular Origin and Therapeutic Targets

Akademisk avhandling för avläggande av teknologie doktorsexamen vid Tekniska fakulteten vid Lunds universitet. Avhandlingen kommer att offentligen försvaras på Astronomiska Institutionen, Sölvegatan 27, Lund, Lundmarksalen, fredagen den 4 juni 2004 kl 13.15. This thesis is based upon the following papers, which are referred to in the text by their Roman numeral (I-IV). (2002) " Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared to subpopulations of normal human B cells " Cancer Res 62(15): 4398-405. " Mantle cell lymphomas overexpress CCL4, CCL5 and 4-1BB ligand and show evidence of an activated B cell origin " (submitted 2004) " Increased expression of Ki-67 in mantle cell lymphoma is associated with deregulation of several cell cycle regulatory components, as identified by global gene expression analysis " Haematologica. In press, 2004. " Transcriptional profiling and assessment of cell lines as in vitro models for mantle cell lymphoma " (submitted 2004) The articles are reproduced with the permission of the publishers. 7 Abbreviations AIDS acquired immunodeficiency syndrome ALL acute lymphoblastic leukaemia AML acute myeloid leukaemia Apaf-1 apoptotic protease activating factor-1 ATM ataxia telangiectasia mutated BCR B cell receptor CCL centrocytic lymphoma CDK4 cyclin-dependent kinase 4 cDNA complementary DNA CHOP cyclophosphamide, doxorubicin, vincristine and prednisone CLL chronic lymphocytic leukaemia/lymphoma CNS central nervous system DLBCL diffuse large B cell lymphoma EBV Epstein-Barr virus FDC follicular dendritic cell FL follicular lymphoma FM follicular mantle GC germinal centre GS growth signal HEV high endothelial venule HIV human immunodeficiency virus hTERT human Telomerase Reverse Transcriptases Ig immunoglobulin MCL mantle cell lymphoma MMP matrix metalloproteinase MZ marginal zone NHL non-Hodgkin's lymphoma pRb retinoblastoma protein RAG-1 recombination activating gene 1 V H immunoglobulin variable heavy chain gene 8 Transcriptional analysis of mantle cell lymphoma 9 Chapter 1