Mantle cell lymphoma : studies of predictive markers, the role of the microenvironment in disease development and identification of new potential targets for therapy

Sammanfattning: Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma and accounts for 5-10 % of all non-Hodgkin lymphomas (NHL). In Sweden, the incidence of NHL is 21.6 and 15.3 per 100 000 persons for men and women, respectively, which result in almost 100-200 new MCL cases per year. MCL was considered an own entity in 1994 and is characterized by the gene translocation t(11;14)(q13;q32), CCND1/IGH ,that occurs in pre-B cells and increases the expression of cyclin D1. Cyclin D1 drives the cell cycle thus promoting cell proliferation. This is believed to be the first oncogenic event in MCL. Additional oncogenic events are needed for MCL pathogenesis including aberrations in DNA-damage repair, cell cycle control and cell survival pathways. MCL is also dependent on the tissue microenvironment in order to survive, since MCL cells kept in vitro quickly die if not co-cultured with e.g. stromal cells. The typical MCL patient is male and 65-70 years old at the time of diagnosis. The disease is often spread to bone marrow, blood, lymph nodes, Waldeyers ring, gastro intestinal tract and spleen. MCL usually respond well to first line treatment but then invariably relapses. In my studies, I have used a well characterized population-based cohort of MCL patients from the Stockholm region. I have used this cohort to study various aspects of the disease, including potential markers to identify a more indolent disease course, the impact of the lymphoma tissue microenvironment and the cannabinoid receptors and the role of gender, comorbidities and choice of therapy in relation to outcome. In paper I and paper IV we identify a subpopulation of MCL patients with a more indolent disease course, not needing therapy for at least two years after diagnosis. Several studies have tried to find a good marker predicting indolent disease, and the transcription factor SOX11 was initially suggested to carry such information. In paper I, we verify known prognostic markers such as age, elevated ECOG performance status, elevated lactate dehydrogenase (LDH) and high p53 expression, while SOX11 could not be used alone to predict disease course. In paper IV we found that women are older and more often have elevated LDH at the time of diagnosis. After introduction of the monoclonal CD20 antibody rituximab to first line therapy, the OS increased. In contrast to most studies we found that male gender was a positive prognostic factor. The median overall survival (OS) for all patients was 3,9 years and for those receiving or were intended for ASCT (27,3%) 16,3 years. In paper II we report that the tissue microenvironment in MCL correlate to patient outcome. In MCL samples, T cells were fewer than in reactive lymph nodes and higher CD4+/CD8+ ratio correlated to longer OS. In paper III we study the impact of the two cannabinoid receptors type 1 and type 2 (CB1 and CB2) which are upregulated in MCL cells compared to non-malignant B cells. We analysed CB1, CB2 and the enzymes involved in synthesis and metabolism of the cannabinoid receptor agonist anandamide (NAPEPLD and FAAH, respectively). All MCL had upregulated expression of NAPEPLD and most had low expression of FAAH compared to normal B cells thus favouring increased anandamide levels. Further, we found high expression of CB1 and high CB1 expression correlated to SOX11-positivity while low CB1 expression correlated to leucocytosis and lymphocytosis. High amount of FAAH also correlated to leucocytosis and lymphocytosis and to p53-positivity. We found no prediction for outcome, but the endocannabinoid system is still a potential target for therapy that needs to be investigated further.