Advisor(s)
Rui Lu
Committee Member(s)
Erin Ahn
Ravi Bhatia
School
Joint Health Sciences (Interdisciplinary)
Document Type
Thesis
Department (new version)
Joint Health Sciences
Date of Award
9-9-2024
Abstract
Acute myeloid leukemia (AML) is a blood cancer marked by the rapid growth of abnormal myeloid cells, driven by various genetic mutations. AML accounts for approximately 1% of all cancers and presents complicated prognosis and treatment. Menin inhibitors have shown potential in targeting AML. However, resistance to these inhibitors presents a significant clinical obstacle, as patients treated with menin inhibitors are increasingly developing resistance to the treatment. Using CRISPR-Cas9 mediated screening, we identified an epigenetic regulator contributing to resistance against menin inhibitors in AML. Utilizing knockout (KO) models of the epigenetic regulator in-vitro, ex-vivo, and in-vivo, we observed a growth advantage and resistance to menin inhibitors in AML. Cells deficient of the epigenetic regulator displayed hindered differentiation, as indicated by lower levels of the myeloid differentiation marker CD11b after menin inhibitor treatment. Comprehensive RNA sequencing (RNA-seq) of AML cell lines revealed significant changes in gene expression profiles, highlighting differentially ex-pressed genes (DEGs) and pathways linked to drug resistance. Gene Ontology analysis uncovered that a critical signaling pathway may be affected in KO cells. Future research will aim to validate these findings and investigate combination therapies to address resistance in AML. This study sheds light on the molecular mechanisms underlying resistance to menin inhibitors, paving the way for the development of more effective therapeutic approaches for AML.
ProQuest ID
Recommended Citation
Srinivas, Neha, "A Histone Methyltransferase Contributes to Treatment Resistance in NPM1c AML" (2024). All ETDs from UAB. 7620.
https://digitalcommons.library.uab.edu/etd-collection/7620
