TY  - UNPB
ID  - discovery10205407
N2  - 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.
UR  - https://discovery.ucl.ac.uk/id/eprint/10205407/
PB  - UCL (University College London)
M1  - Doctoral
A1  - Alhawaj, Ali Fouad Yassin
TI  - Integrative Genomic Analysis of  Cytogenetically Normal Acute Myeloid Leukaemia
EP  - 184
AV  - public
Y1  - 2025/02/28/
N1  - 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.
ER  -