LIMR Haematology: Oncogenic mechanisms causing malignant transformation of B cells and plasma cells

Summary

Cancers of B cells and plasma cells, lymphomas and multiple myeloma, can be very aggressive, and often the cancer rapidly reoccurs after standard therapy. In the UK alone, approximately 14,000 lymphoma and 6,000 myeloma cases are diagnosed each year, with 5,000 and 3,000 deaths, respectively. Thus, there is a clinical need for more effective therapies against these malignancies, which requires a better understanding of the biology of these cancers.

Towards this goal, it is important to understand the molecular processes underlying the oncogenic transformation of B cells and plasma cells into lymphomas and multiple myeloma, respectively. This knowledge will provide the scientific 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 constitutive 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, currently there are no therapies in the clinics that specifically target NF-κB, mostly because global inhibition of the entire NF-κB signaling pathway in the body results in systemic toxicity. Therefore, understanding 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.

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 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 multiple 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 next generation sequencing (NGS) of mRNA and chromatin immunoprecipitation sequencing (ChIP-seq) or ATAC-seq analyses through bioinformatics approaches. Identified targets will be validated and tracked in patient biopsies, which are obtained from the Leeds Teaching Hospital.

Techniques associated with this project:

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.

This project is part of the International PhD Academy: Medical Research.

In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.