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Title: Genetic and functional characterisation of Immunoglobulin Heavy Chain Locus-CCAAT enhancer binding protein B-Cell acute lymphoblastic leukaemia
Author: Mašić, Dino
ISNI:       0000 0004 6352 416X
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2016
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B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is a heterogeneous disease in which patient outcome is influenced by genetic lesions. This outcome has improved due to increasingly tailored treatment regimens, selected through risk stratification by use of cytogenetic, copy number alterations (CNAs) classifiers, genomic, and molecular data. Translocations involving the Immunoglobulin Heavy Chain Locus (IGH) comprise 5% of BCP-ALL and lead to overexpression of juxtaposed genes, due to the powerful IGH enhancer elements. Multiple IGH partner genes have been described in BCP-ALL, including five members of the Ccaat Enhancer-Binding Protein (CEBP) transcription factor family. A cohort of 33 IGH-CEBP BCP-ALL patients was identified including 11 IGH-CEBPD, 10 IGH-CEBPA, 8 IGH-CEBPB, 3 IGH-CEBPE and 1 IGH-CEBPG patients, comprising 19% of the IGH cohort, and 1% of ALL as a whole. The patients displayed variation between individual CEBP subgroups, with IGH-CEBPB patients showing higher white blood cell counts (WBC), higher relapse rates, higher number of CNAs and older age than other CEBP patients. The CEBPD subgroup included mostly younger patients, under the age of 10 years, and had the lowest number of CNAs per patient. Deletions of CDKN2A/B were the most commonly occurring CNA followed by intragenic exon 4-7 deletions of IKZF1, which were found exclusively in the IGH-CEBPB and IGH-CEBPD subgroups (p=0.04). A novel intragenic deletion of the tyrosine kinase gene, ABL2, was found in four patients in the cohort, which may represent a deletion unique to this subgroup. This finding in combination with the IKZF1 deletions is suggestive of a BCR-ABL1-like profile. Retroviral expression of the CEBPD gene in CD34+ cells was found to hinder proliferation in transduced cells, potentially through cell cycle arrest via the RB/E2F pathway. RNA sequencing analysis of two IGH-CEBP patients showed very different expression profiles, suggesting two mechanisms of oncogenesis in IGH-CEBP patients: one through inactivation of the CEBP function, leading to deregulation of cell cycle and differentiation control, and another through upregulation of inflammatory factors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available