Molecular Targeting of High-Risk Pediatric Leukemia: Identification of Targets and Biological Implications for Therapy
Date
2024-11-26
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Acute leukemias with KMT2A (mixed-lineage leukemia or MLL) rearrangements are associated with poor prognosis and high relapse rates, particularly in infant and pediatric populations. The outcomes for patients with KMT2A-rearranged (KMT2A-r) leukemia remain suboptimal, underscoring the urgent need for novel, targeted therapeutic approaches. This thesis focuses on disrupting key molecular interactions within the KMT2A fusion protein complex that drives leukemogenesis while characterizing novel preclinical models to facilitate targeted drug discovery. By utilizing established cell line models, cell-based assays and drug combination studies, this study demonstrated the therapeutic potential of inhibiting the interaction between KMT2A fusion protein and a transcriptional kinase, CDK9. In addition, the study demonstrates that targeting CDK9 can decrease venetoclax and steroid resistance in KMT2A-r leukemia. Furthermore, this thesis investigates the biological implications of treatment induced differentiation, with a focus on identifying therapeutic strategies to treat KMT2A-r leukemias. Our results demonstrate that menin inhibitor induced differentiation in KMT2A-r cells carries a distinct inflammatory profile with elevated secretion of HMGB1 and IL-8. These cytokines are associated with promoting migratory responses. In addition, our findings showed a synergistic interaction between menin inhibition and corticosteroids, which is the first line treatment for patients with differentiation syndrome. In parallel, the study evaluates the efficacy of the ETS inhibitor TK216, targeting SPI1 overexpression in pediatric AML and B-ALL leukemias, with the goal of uncovering its therapeutic potential in high-risk pediatric leukemia. The research presented herein offers a framework for developing feasible novel therapeutic strategies for KMT2A-r leukemias, building on a foundation of preclinical modeling and mechanistic insights that may inform future clinical interventions.
Description
Keywords
Oncology, Pediatric, Therapeutics
Citation
Sharma, R. (2024). Molecular targeting of high-risk pediatric leukemia: identification of targets and biological implications for therapy (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.