%0 Thesis
%9 Doctoral
%A Alhawaj, Ali Fouad Yassin
%B Haematology
%D 2025
%F discovery:10205407
%I UCL (University College London)
%P 184
%T Integrative Genomic Analysis of  Cytogenetically Normal Acute Myeloid Leukaemia
%U https://discovery.ucl.ac.uk/id/eprint/10205407/
%X Acute Myeloid Leukaemia (AML) is a haematological malignancy characterized by increased   proliferation and blocked differentiation of haematopoietic progenitors. Cytogenetically   normal AML (CN-AML) accounts for approximately 50% of all AML cases, with a 5-year survival   rate of approximately 50%. Approximately 40% of patients exhibit primary resistance to   induction chemotherapy; however, the molecular basis remains poorly understood.   Additionally, high SETBP1 expression has been implicated in AML development, although the   underlying mechanism remains unclear. This thesis aimed to explore the genomic and   transcriptomic profiles of primary-resistant CN-AML in adults, and SETBP1 allele-specific   expression (ASE) as a potential cause of high SETBP1 expression.   Through whole-exome and RNA sequencing of resistant and matched remission samples, we   identified a high presence of UBTF-TD in adult CN-AML (12%) and a higher incidence of WT1   mutations in the resistant versus remission cohorts (29% vs. 10%, p=0.005). However, CRISPR   knockout of WT1 in a 416B mouse model did not confer resistance to Cytarabine or   Daunorubicin.   RNA sequencing indicated enrichment of senescence signatures in the resistant cohort, along   with novel gene fusions of LATS2-ZMYM2 (20.9%) and LATS2-HMGB1 (14.3%) in CN-AML.   Lastly, integrative genomic and transcriptomic analyses revealed GATA2 and SETBP1 ASE,   including a novel non-coding SETBP1 mutation, potentially driving its high expression.   Future studies are required to validate UBTF-TD lesions and refine the WT1 knockout,   potentially revealing new resistance mechanisms amenable to treatment. LATS2 fusions also   require validation to clarify their impact on the tumour-suppressive Hippo pathway. Finally,   long-read and whole-genome sequencing may reveal additional mechanisms underlying   GATA2 pathogenic expression, whereas functional assays of the novel non-coding SETBP1   variant may elucidate its role in driving AML. These findings may ultimately refine the   prognosis and inform new therapeutic strategies for high-risk CN-AML.
%Z Copyright © The Author 2025.  Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/).  Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms.  Access may initially be restricted at the author’s request.