Zareian, Nahid; (2015) Dissecting the role of cooperating genetic lesions in acute leukaemia. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

My thesis investigates cytogenetics and molecular genetics of acute leukaemia. In the cytogenetics part, I aimed to map and characterize recurrently altered regions of the RUNX1 and TET2 genes in myeloid malignancies by fluorescence in situ hybridization (FISH) technique using gene specific in house designed fosmid/BAC probes, and to investigate whether this FISH technique could confirm the presence of cryptic genome lesions that were previously identified by aCGH screening. I developed a sensitive FISH method that confirmed these genome imbalances in all cases with a variety of sizes comparable to aCGH. Consequently the strategy I propose for therapy response monitoring in myeloid malignancies starts with FISH analysis by addressing a selected abnormality depending on patient’s history. In cases where FISH provides evidence for persistent disease, aCGH is recommended to assess the level of genome complexity and evolution of the size of genome loss. Second part of this thesis investigates molecular genetics of acute lymphoblastic leukaemia (ALL). Deletion in the IKZF1 gene is common and prognostic of poor outcome. I aimed to assess the utility of the IKZF1 exons 4-7 deletion (IKZF1 Δ4-7) as a minimal residual disease (MRD) marker in adult BCR-ABL1-negative ALL and to investigate the contexts and mechanisms by which IKZF1 Δ4-7 encoded protein, IK6, contributes to enhanced leukaemogenesis. I showed that IKZF1 Δ4-7 was typically subclonal and instable during the course of disease, signifying that the positive suggestion of IKZF1 Δ4-7 as an MRD marker is not encouraging. Overexpression of IK6 appeared to play a role in higher growth rate, drug resistance and increased DNA instability and this role may be more pronounced in the presence of BCR-ABL1. By contrast, the poor risk phenotype conferred by IK6 expression in BCR-ABL1-negative ALL cannot be elucidated further by this dataset suggesting that alternative co-operating lesions are in action.

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