How do B cells and plasma cells transform into cancers?

B cells and antibody-secreting plasma cells protect us from infections by bacteria and viruses but can occasionally transform into cancers. The cancers of B cells and plasma cells, called lymphoma and multiple myeloma, can be very aggressive, and often the cancer comes back soon after therapy. In the UK alone, approximately 14,000 lymphoma and 6,000 multiple myeloma cases are diagnosed each year. Thus, there is a clinical need for more effective therapies in the treatment of lymphoma and multiple myeloma, which requires a better understanding of the biology of these cancers.<br />

<p style="margin-bottom:13px">Towards this goal, it is important to understand exactly how B cells and plasma cells transform into lymphomas and multiple myeloma at the molecular level. This knowledge will provide the basis for improved therapies and for personalized medicine strategies in the treatment of these aggressive malignancies. </p> <p>A major contributor to the development of aggressive lymphomas and multiple myeloma is signalling through the nuclear factor-κB (NF-κB) signal transduction pathway due to genetic, cancer-causing mutations. Consequently, these observations identify targeting of cancerous NF-κB signalling as a treatment strategy. However, currently there are no therapies in the clinics that specifically target NF-κB, mostly because the inhibition of the entire NF-κB signalling pathway in the body results in severe toxicity. Therefore, understanding exactly how NF-κB signalling functions in the tumour cells is crucial in order to identify the precise, therapeutically targetable molecules of this pathway.</p> <p>Since NF-κB activation ultimately leads to the nuclear translocation of five different NF-κB transcription factor subunits that transcribe target genes, a strategy for inhibiting cancerous 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 transcriptional target genes. We have published and preliminary data demonstrating that certain 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.    </p> <p>This project is aimed at identifying the role of the distinct NF-κB transcription factors in subtypes of lymphomas and multiple myeloma where genetic mutations activate the NF-κB signalling pathway. 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 next generation sequencing (NGS) of mRNA and chromatin immunoprecipitation sequencing (ChIP-seq) or other genomic methods (e.g., ATAC-seq analyses) through bioinformatics approaches. Identified targets will be validated and tracked in patient biopsies, which are obtained from the Leeds Teaching Hospital. </p> <p>In addition to NGS (next generation sequencing), ChIP-seq/ATAC-seq and bioinformatics, validation of the identified targets will involve a broad range of molecular and cell biology techniques, including cloning, PCR, gel electrophoresis, western blotting, ELISA, flow cytometry, immunohistochemistry, and metabolic flux analyses.</p> <p> </p> <h2><strong>REFERENCES:</strong></h2> <p><br /> <a href="https://pubmed.ncbi.nlm.nih.gov/30380749/">Kennedy R, Klein U. Aberrant Activation of NF-κB Signalling in Aggressive Lymphoid Malignancies.</a> Cells. 2018 Oct 30;7(11):189. doi:10.3390/cells7110189. PMID: 30380749 </p> <p>Pasqualucci L, Klein U. <a href="https://pubmed.ncbi.nlm.nih.gov/36289712/">NF-κB Mutations in Germinal Center B-Cell Lymphomas: Relation to NF-κB Function in Normal B Cells.</a> Biomedicines. 2022 Oct 1;10(10):2450. doi: 10.3390/biomedicines10102450. PMID: 36289712</p> <p><a href="https://pubmed.ncbi.nlm.nih.gov/36867577/">Cytokine receptor IL27RA is an NF-κB-responsive gene involved in CD38 upregulation in multiple myeloma.</a> Brownlie RJ, Kennedy R, Wilson EB et al. &, Klein U. Blood Adv. 2023 Aug 8;7(15):3874-3890. doi: 10.1182/bloodadvances.2022009044. PMID: 36867577</p>

<p>Formal applications for research degree study should be made online through the <a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">University's website</a>. Please state clearly in the research information section that the research degree you wish to be considered for is <strong>How do B cells and plasma cells transform into cancers? </strong>as well as<strong> Prof Ulf Klein and Dr Gina Doody </strong>as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

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