Wasim, Laabiah; (2023) Survival pathways harnessed by Follicular Lymphoma and Transformed Follicular Lymphoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The genetic processes that allow for B-cell humoral immunity can also result in genetic aberrations leading to B-cell lymphoma. Follicular lymphoma (FL) is a common non-Hodgkin’s lymphoma and while FL is indolent, it can transform into an aggressive disease. This thesis investigates the survival pathways harnessed by FL and tFL, namely how features of B-cell biology, such as the role of the BCR itself, downstream signalling, and transcriptional states, are harnessed to drive lymphomagenesis, maintenance and transformation. One understudied functional characteristic of the BCR is isotype usage, with lymphomas generally favouring IgM expression. To investigate the role of the IgG isotype, I conducted a mutational analysis in a primary lymphoma dataset and identified novel mutations, enriched in the tFL molecular subtype, in the IgG cytoplasmic tail that render the IgG receptor similar to IgM. I demonstrated that IgG BCR may be inferior to IgM in supporting tFL growth through the tonic signalling pathway, and these mutations may be a mechanism to enhance competitiveness in class-switched lymphomas. Another distinct feature of the FL-BCR is high-mannose variable region glycosylation. These unprocessed sugars may allow for FL cell maintenance in-vivo through interaction with lectin receptors on immune cells in the tumour microenvironment. Previous research has shown that the lectin DC-SIGN can engage FL-BCRs and trigger downstream signalling. To further understand the signalling differences, I investigated the biophysical differences between DC-SIGN and antigen engagement on immune synapse formation and actin dynamics, demonstrating that DC-SIGN stimulation results in unique immunological synapse formation. Finally, there are multiple pathways of FL transformation, one such high-grade transformation results in TdT+ B-lymphoblastic leukaemia (B-LBL) that interestingly displays features of dedifferentiation into a “pre-B-cell” phenotype. Through conducting a genome-wide CRISPR screen on a TdT+ tFL line, I identified MYB as a novel putative regulator of B-LBL cell growth and maintenance of the de-differentiated cell state.

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