El-Sharkawi, D; (2016) Studies to Investigate Epigenetic Factors in Acute Myeloid Leukaemia. Doctoral thesis , UCL (University College London).

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Abstract

Acute myeloid leukaemia (AML) is a heterogeneous disease with numerous recurrent cytogenetic and molecular abnormalities. This heterogeneity is reflected in the variation in clinical outcome seen in patients. This disparity in outcome is also seen within groups of patients who have the same mutation or no known molecular abnormalities. To investigate whether the DNA methylation profile of samples can provide prognostic information, the methylome of forty cytogenetically normal AML samples that were wild-type for NPM1 and FLT3 was analysed, 20 were from patients with chemosensitive disease and 20 with chemoresistant disease. Unsupervised cluster analysis revealed the DNA methylation profile to be most associated with underlying CEBPA genotype hence a CEBPA signature was created using the 25 CpG sites that differed the most between wild-type (n=30) and classic CEBPADM (double mutant) samples (n=10). Two follow-up cohorts were analysed, validating the initial signature in differentiating classic CEBPADM samples from wild-type. CEBPASM (single mutant) samples had profiles more similar to the CEBPAWT (wild-type) signature. Non-classic CEBPADM samples with at least one mutation leading to loss of function of the C terminal were associated with a CEBPA mutant methylation profile. Methylation of the CEBPA promoter was not associated with a classic CEBPADM methylation profile in eight of the nine cases exhibiting hypermethylation. The ASXL1 gene, known to have a role in histone regulation, was screened in 371 patients using denaturing HPLC. The overall mutation rate was 9%. Overall survival was significantly lower in patients with an ASXL1 mutation, however the mutation was associated with secondary disease and older age, and thus in multivariate analysis mutations in ASX L1 lost significance. These studies indicate that epigenetic factors are closely linked to other prognostic traits such as age or underlying molecular status of the AML. Given this association, DNA methylation could play an important role in assessing the significance of different types of mutations.

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