About the Project
Towards this goal, identifying the molecular processes underlying the malignant transformation of B cells and plasma cells is critical for understanding the development of lymphomas and multiple myeloma. This knowledge will provide the rationale and molecular basis for personalized medicine in the treatment of these aggressive malignancies.
A major player in the pathogenesis of aggressive lymphomas and myeloma is aberrant signaling through the nuclear factor-κB (NF-κB) transcription factor complex due to genetic mutations. These observations identify targeting of aberrant NF-κB signaling as a treatment strategy. However, the NF-κB-signaling cascade is extremely complex, consisting of two separate pathways and several distinct transcription factors. Unravelling the complexity of NF-κB signaling in the tumour cells is crucial in order to identify the precise, therapeutically targetable molecular components of this pathway. This is particularly important because global inhibition of the entire NF-κB signaling pathway results in systemic toxicity.
Since NF-κB activation ultimately leads to the nuclear translocation of five different NF-κB transcription factor subunits that transcribe target genes, a conceivable strategy for inhibiting aberrant NF-κB activation in a more selective, less toxic way would be to target the downstream transcription factors that are oncogenic in the cancer, or their target genes. We have published and preliminary data demonstrating that particular normal B cells and certain lymphoid malignancies can indeed depend for their growth and survival on the activity of distinct NF-κB subunits rather than on the activation of all NF-κB subunits.
This project is aimed at identifying the role of the distinct NF-κB transcription factors in subtypes of lymphomas and myeloma. The separate NF-κB subunits will be functionally ablated by gene silencing and CRISPR-knockout in cell lines using retrovirus-mediated approaches, which will identify their requirement for tumour-cell growth and survival. Transcriptional targets of the subunits will be identified by integrating RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses through bioinformatics approaches. Identified targets will be validated and tracked in patient biopsies.
2) Heise, N., N.S. De Silva, K. Silva, A. Carette, G. Simonetti, M. Pasparakis & U. Klein. (2014) Germinal center B-cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits. Journal of Experimental Medicine 211:2103.
3) De Silva, N.S. & U. Klein. (2015) Dynamics of B cells in germinal centres. Nature Reviews Immunology 15:137.
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