Dissecting and Modeling Oncogene Dependent Molecular Mechanisms in Lymphoma Genesis and Progression
by Elisabeth Hand
Date of Examination:2013-10-15
Date of issue:2013-11-18
Advisor:Prof. Dr. Dieter Kube
Referee:Prof. Dr. Mikael Simons
Referee:Prof. Dr. Peter Burfeind
Persistent Address:
http://dx.doi.org/10.53846/goediss-4158
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Abstract
English
Aggressive Non-Hodgkin lymphomas (aNHL) are a heterogeneous group of lymphomas. The constellation of oncogenic pathway activities can vary in patients with the same malignant disease. The pathological mechanisms behind the current criteria to distinguish individual aNHL subtypes are still poorly understood. Molecular models depicting the dynamics of oncogenic signaling and cross talk of the pathways can help to obtain a better understanding of lymphoma pathogenesis. Thereby the development of future targeted therapies, that will have to intervene with specific signaling modules to reverse pathway deregulation, will be enabled. We postulate that the description of a time-resolved global gene expression change provides new insights into the dynamics of oncogenic signaling and that the intervention into pathway intersections allows identifying new essential pathway nodes and cross talks for targeted therapies. To gain closer insight into distinct cell signaling networks and their relevance for NHL subtypes, firstly, high-dimensional data of time-resolved gene expression changes in BL2 cells induced by BCR or CD40 activation were generated. By using a newly established computational method we were able to describe 20 disjoint sets of genes to group their time courses. 15 significant sets of genes were identified for BCR stimulated samples and 5 significant sets of genes for CD40 activated samples, all displaying distinct time courses. We discovered a co-repression of LEF1, PTCH1 and NOTCH1 by activation of the B cell receptor. Functional assays revealed that BL cells are not responsive to Sonic hedgehog stimulation, but evidence is provided for a c-Myc-driven non-canonical regulation of this pathway. Furthermore, a working model for a causality network of BCR induced gene expression correlations was compiled. In addition, sustained activated BCR signaling induced a change of the gene expression profile towards a certain ‘DLBCL-likeness’. Therefore, a first step to develop a model displaying the causative factors for the non-mBL signature is provided. Secondly, the gene expression changes of BCR or CD40L stimulated BL2 cells after chemical inhibition of Tak1, JNK, p38 and IKK2 were monitored on the whole genome level. In BCR stimulated cells the activity of PI3K and Mek1/2 was as well inhibited. Additional biochemical analyses supported the view that Tak1 is a pivotal modulator of both CD40 and BCR mediated p38 and NF-κB signaling. Moreover, using (5Z)-7-Oxozeanol as well as TAK1-directed siRNA to inhibit Tak1 activity, a corresponding Tak1-Erk1/2 subnetwork was described. Thus, the present study and the herein allocated data provide deep insight into oncogenic pathway activities and enable a large variety of continuing studies, which may help to obtain a better understanding of the biology of lymphoma.
Keywords: aNHL; Burkitt Lymphoma; DLBCL