Transcriptional Profile of Cohesin Complex Mutations in the Background of NPM1 AND RUNX1-RUNX1T1 AML
Date of Award
Fall 2022
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Mathematical and Statistical Sciences
Program
Bioinformatics
First Advisor
Rao, Sridhar
Second Advisor
Maadooliat, Mehdi
Third Advisor
Anne, Clough
Abstract
Acute Myeloid Leukemia is a cancer of the blood, characterized by a heterogenous mixture of disease causing mutations. Mutations of the cohesin complex is a group of such mutations and occur alongside several other driving mutations in the development of Acute Myeloid Leukemia. This thesis specifically focuses on cohesin complex mutations in the context of concurrence with NPM1 mutation and the Core Binding Factor (CBF) mutation RUNX1-RUNX1T1 in three distinct components. The first two components involved Differential Expression Analysis (DEA) to identify significantly differentiated genes in each model, followed by Gene Set Enrichment Analysis (GSEA) to identify Gene Ontology (GO) terms associated with the significantly expressed genes. The third component involved a cross analyses of the significantly expressed genes from both the NPM1 and CBF analyses to identify genes enriched in both primary analyses and further Gene Ontology Overrepresentation Analysis was used to characterize the gene ontology terms shared in the identified gene set.In the DEA of NPM1mutatant + cohesin mutant vs. NPM1 wild-type mice there were 239 genes up-regulated NPM1-cohesin mutant model and 126 down- regulated genes identified. DEA of cohesin mutant + RUNX1-RUNX1T1 vs. cohesin wild-type RUNX1-RUNX1T1 from a cohort of pediatric and adolescent patients revealed 212 upregulated genes and 472 downregulated significantly differentiated genes identified. The cross analyses of differentially expressed genes from both the NPM1 and CBF analyses completed with an analyses for enrichment of the CBF gene set in the NPM1 up and down regulated gene sets revealed 55 genes that were of the core GSEA enrichment. From the 55 genes a number of GO terms were identified from the Biological Process, KEGG and Reactome GO collections. Network and clustering analyses further was used to identify patterns in the representation of the Biological Process GO terms identified. The predominant cluster was representative of GO terms involving immune, inflammatory, and leukocyte processes. The emphasis on immune/inflammatory dysregulation from the outcome in the analyses serves as a potential point of interest in characterizing the functional role of the cohesin complex in future studies.