Chronic lymphocytic leukaemia (CLL) and diffuse large B cell lymphoma (DLBCL) make up more than half of all the newly diagnosed cases of non-Hodgkin’s lymphoma (NHL), the 6th most common cancer in the UK. Among these cases of CLL and DLBCL there will be some which harbour malignant cells bearing deletion of the short arm of chromosome 17p (del(17p)), marking the disease that these patients suffer as high-risk because the malignant cells can easily build resistance to therapy and behave in a clinically aggressive manner. Whilst therapy resistance can be explained by the functional loss of TP53, aggressive behaviour of the malignant cells cannot. In fact, we know very little about the impact of del(17p) on cells because there is a lack of cell models with which to study this deletion. Our preliminary work so far shows we are able to use CRISPR/Cas9 to remove large sections of genomic DNA, and we have successfully removed the TP53 gene from 17p in cells. This work therefore supports the aim of this project: to use CRISPR/Cas9 to create cell line models of CLL and DLBCL which bear deletion of chromosome 17p in order to study how such deletion impacts gene expression and cell response to therapy. Gene dropout screens of the 394 genes that are present on 17p will provide insight into how these genes function to promote cell resistance to therapy as well as maintain cell survival, potentially identifying synthetic lethalities that can be exploited for therapeutic use.
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