A Molecular Dissection of Mantle Cell Lymphoma - From gene expression analysis to functional evaluation of selected targets

Abstract: Mantle cell lymphoma (MCL) is an aggressive form of B-cell lymphoma (BCL) with poor clinical outcome. In this thesis, which is based upon five original papers, different approaches have been used to pinpoint and investigate molecular events that promote MCL tumor growth, progression or resistance to treatment. The aim has been to identify novel targets with the potential to eradicate malignant cells, including more resistant cell clones.

In Paper I-III, a previously defined MCL specific disease marker, SOX11, was functionally studied. Our results demonstrate that SOX11 is a tumor suppressor-like gene, exhibiting a central role in MCL tumor growth control. Using gene expression studies, we identified HIG-2 and CD24 as important downstream targets of SOX11, and due to their cell surface localization on MCL cells they are considered of potential therapeutic interest. Moreover, using functional screening with substances targeting components of the WNT pathway, WNT-related targets with SOX11-dependent growth regulation were identified. One of the targets, V-ATPase, a pH regulator, was shown to be sensitive to SOX11 levels. Validation studies confirmed that V-ATPase is localized on the plasma membrane of MCL cells, and is thus an interesting candidate for antibody-based treatment.

Despite the high response rate of MCL patients to initial treatment, a large number of patients relapse with a more treatment resistant disease. In Paper IV, the molecular mechanism behind developed resistance to cytarabine, a commonly used chemotherapeutic in treatment of MCL was investigated. Our results show that resistance to cytarabine in MCL is mediated by down-regulation of dCK at protein level. Importantly, cytarabine resistant cells were also shown to exhibit cross-resistance to other chemotherapeutic drugs (nucleoside analogues) acting similarly to cytarabine. Considering these findings, patients demonstrating cytarabine resistance in clinic should be offered non-nucleoside analogue based treatment.

Finally, in Paper V, we investigated the presence of a rare population of more treatment resistant cells, identified as side population (SP), in MCL. SP cells isolated from MCL patient material exhibited up-regulated expression levels of the early cell activation markers CD69 and CD44, in agreement with a stem-cell like origin. Of major importance, an enrichment of SP cells was observed in chemotherapy exposed cells, indicating that SP cells have functionally important features, and need to be further investigated in MCL.