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Title: Studies on CEBPA mutations in acute myeloid leukaemia
Author: Green, C. L.
ISNI:       0000 0004 2738 8236
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2012
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Acute myeloid leukaemia (AML) is a highly heterogeneous disease with regard to clinical outcome, and molecular markers with prognostic impact can be used to stratify patients for risk-adapted therapy. CEBPA mutations have been associated with a favourable prognosis, however several questions remained, in particular whether one (CEBPA-single) or two (CEBPA-double) mutations were necessary for this benefit, and their interaction with other molecular markers. A method of detecting CEBPA mutations in patient samples using denaturing HPLC was developed and the CEBPA status of 1427 young adult AML patients (median age 43 years, range 15-68 years) determined. Overall, 107 (7%) were CEBPA-mutant: 48 (45%) CEBPA-single and 59 (55%) CEBPA-double. The majority of CEBPA-double patients (83%) had an out-of-frame insertion/deletion in the N-terminus and a mutation in the C-terminal DNA-binding/leucine zipper domains (DBD/LZD) that were on different alleles as determined by cloning. By contrast, mutations in CEBPA-single cases were distributed across the gene. CEBPA-double patients were less likely to have a FLT3/ITD (P=.04) and highly unlikely to have an NPM1 mutation (P<.0001) compared to CEBPA-WT/CEBPA-single cases. Eight year overall survival (OS) was higher in CEBPA-double patients compared to CEBPA-WT and CEBPA-single cases (54%, 34%, 31%, respectively, P=.004). In multivariate analyses, CEBPA-double, but not CEBPA-single, was an independent favourable factor for OS (P=.004) and relapse (P=.02). However, this benefit was completely lost in the presence of a FLT3/ITD. The mutant level of 101 mutations was determined by fragment analysis and the majority were of a level consistent with a heterozygous mutation present in most cells. The impact of ten atypical CEBPA mutations on C/EBPα transactivation activity was explored by a luciferase reporter assay. Only mutations affecting the DBD or LZD functional domains had an impact on transactivation activity. This work provides insight into the biology of CEBPA mutations and their use as clinical markers.
Supervisor: Gale, R. E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available