Identifying novel therapeutic vulnerabilities of acute myeloid leukemia molecular subtypes

Acute myeloid leukemia (AML) remains a therapeutically challenging haematological malignancy characterized by genetic heterogeneity and poor outcomes in high-risk populations. Despite recent advances, many AML subtypes exhibit treatment resistance, necessitating novel therapeutic strategies targeting specific molecular vulnerabilities. This thesis investigated therapeutic vulnerabilities across three distinct AML molecular subtypes. First, we evaluated PARP1 inhibition combined with Gemtuzumab ozogamicin in CD33-positive AML. Talazoparib synergistically enhanced Gemtuzumab ozogamicin efficacy by impairing calicheamicin-induced DNA damage repair, leading to enhanced G2/M arrest and DNA lesion accumulation. Notably, even resistant cell lines demonstrated profound reduction in long-term clonogenic capacity. Primary AML samples showed heterogeneous synergistic activity, with strongest effects at 24 hours. Second, we investigated TP53-mutated AML through targeted inhibition of Aurora B kinase, ATR, and BCL-2. The ATR inhibitor combined with venetoclax showed promising synergy in MOLM-13 cells. Transcriptomic analysis revealed systematic cellular dysfunction with repression of 68.8% of pathways including cell cycle, DNA repair, and metabolism, with activation of multiple cell death mechanisms including pyroptosis. However, marked heterogeneity across TP53-mutated models underscored the complexity of this subtype. Third, we investigated NPM1c mutation impact on FLT3 inhibitor sensitivity through engineered cellular models. NPM1c expression enhanced Gilteritinib sensitivity in MOLM-14 cells but not in MV4-11 cells, demonstrating context-dependent modulation. These studies demonstrate that AML therapeutic responses depend on complex interactions between multiple molecular factors not only on single genetic alterations. The PARP inhibitor and Gemtuzumab ozogamicin combination shows translational promise upon biomarker identification. The ATR and BCL-2 inhibitor combination addresses critical unmet needs in TP53- mutated AML. The NPM1c investigation reveals important co-mutational interactions guiding treatment selection. This work advances AML biology understanding, identifies rational combination strategies for high-risk disease, and provides a framework for personalized therapeutic approaches aiding to improved patient outcomes.