Integrative Genomic Analysis of Cytogenetically Normal Acute Myeloid Leukaemia

Abstract

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 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.