Interplays and feedback loops of oncogenic signaling pathways in B cell non-Hodgkin lymphoma
von Isabel Rausch
Datum der mündl. Prüfung:2019-02-14
Betreuer:Prof. Dr. Dieter Kube
Gutachter:Prof. Dr. Dieter Kube
Gutachter:Prof. Dr. Heidi Hahn
EnglischThe B cell receptor (BCR) signaling, required for the survival and maturation of B cells, is one major deregulated pathway in B cell lymphomas. Several mutations are known to enhance the tonic BCR signal in Burkitt lymphomas (BL) or to mimic an activated receptor in some diffuse large B cell lymphomas (DLBCL). While the proximal events and kinases of the BCR signaling are well studied, less is known about the interactions of downstream effector pathways. As the signaling interplays and feedback loops can influence the therapeutic success, this thesis aims for a better understanding of signaling interplays and for an improvement of oncogenic network models of B cell lymphomas. For this purpose, BCR-related pathway interplays were examined by analyzing several protein phosphorylations with a multiplex immunoassay. Our investigations of pathway activations after thirteen defined perturbations revealed positive as well as negative interplays of pathways downstream of the BCR in BLs. During the tonic and active BCR signaling, the PI3K-AKT pathway, essential for many B cell lymphomas, enhanced its own activation probably through a positive feedback to kinases in close proximity of the BCR. We proposed that the positive feedback loop is one explanation for the potent effects of PI3K, AKT and mTOR inhibitors on BL proliferation. Furthermore, two negative feedbacks on the MEK-ERK pathway were detected after BCR activation. Beside ERK1/2 itself, p38 MAPK negatively influenced upstream kinases of ERK1/2. Interestingly, further fine-tuning of the p38 MAPK and ERK1/2 activation was assumed due to the ERK-mediated upregulation of MKK6 which could contribute to p38 MAPK activation. The mentioned feedbacks were generally identified downstream of the BCR signaling in all examined BL and DLBCL cell lines except for the p38 MAPK-dependent attenuation of the MEK-ERK pathway which was not observed in the DLBCL cell line OCI-LY3. In a second approach, the NF-κB and JAK-STAT-dependent proliferation of B cell lymphomas was investigated. Therefore, the signaling network following TLR9 and IL10R stimulation was analyzed by a phosphoproteom analysis. Our results revealed that the simultaneous activation of TLR9 and IL10R changed over 200 protein phosphorylations influencing cell cycle, metabolism and migration. The direct phosphorylation of CDK2 and JNK was suggested to contribute to the proliferative effect after TLR9 and IL10R activation. The signaling interplays and feedbacks identified in this study provide a deeper insight and refinement of the signaling network structure in lymphomas. Additional improvements of computational network models are advantageous to predict signaling alterations by external influences as well as therapeutic responses.
Keywords: non-Hodgkin lymphoma; BCR signaling; pathway interplays and feedback loops