Neoplasia as hypothesised by Dr Virchow is a disease of malfunctioning development, aberrant dif- ferentiation, evolved kinase activity and deregulated gene expression. Noncoding elements such as enhancers provide essential functions in establishing transcriptional gene control. Therapeutic inter- ventions have rarely been successful in treating cancer drug resistance, including non-genetic resistance to Bruton Tyrosine Kinase inhibitors in activated B cell diffuse large B cell lymphoma. Understanding how epigenetic mechanisms are deregulated or rewired to establish an adapted cellular state can be revealed through enhancer-gene regulatory network inference. This project focuses on gene control changes after adaptation to BTK inhibitors.
The first part of my results focuses on the development of a method for improved assignment of enhancers to their target genes from high-resolution Capture Hi-C data. The second part focuses on the definition of BTK-response genes and enhancers in a model of healthy B cell activation. The third part capitalises on these results to study transcriptional, epigenetic and signalling changes between BTK inhibitor susceptible and resistant lymphoma cells.
I show that the susceptible and resistant cells have distinct gene expression patterns even in the absence of ongoing BTKi treatment. However, the majority of BTK-response genes remain expressed in resistant cells even upon BTKi treatment. Non-coding elements and proteins involved in transcrip- tional regulation are deregulated upon acquisition of resistance. Transcription factor kinase network inference provides a narrowed scope of potential transcription factors and kinases whose activity could rewire the ABC-DLBCL cell model state. Gene regulatory network inference delineates key transcrip- tion factors that could be contributing to ‘stable’ gene regulatory state that drives resistance of cancer cells. Future work could be aimed at understanding key drivers of different regulatory states and at establishment of drug-resistant cancer metaplastic state over time and how it can be perturbed to develop novel therapeutic targets.