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Title: Investigation of cell cycle status in patients with acute myeloid leukaemia
Author: Sellar, R. S.
ISNI:       0000 0004 7229 3850
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Acute myeloid leukaemia (AML) is a biologically and clinically heterogeneous disease. Studies investigating heterogeneity in cell cycle status and response to treatment have been inconsistent, did not take into account the molecular features of the disease, and used blasts derived from aspirates (BMA) or peripheral blood (PB). The work in this thesis used the expression of the DNA replication licensing factors MCM2 (positive in non-G0 cells) geminin (positive in S/G2/M phase) in combination with MIB-1 (actively cycling cells) as assessed by immunohistochemistry and immunocytochemistry to define the cell cycle status of the blasts from PB, BMA, and biopsies (BMT). It shows that the majority of blasts in PB exist in a G1-arrested state and these blasts cause results derived from BMA or PB to significantly underestimate disease proliferation. Further experiments using flow cytometry and RNA sequencing support these conclusions and demonstrate that accurate assessment of cell cycle status in patients requires the use of BMT. A cohort of 181 patients with AML and available BMT for the assessment of DNA replication licensing factors was identified and defined for clinical, cytogenetic, and molecular features, and clinical outcome. The features of this cohort were consistent with those from large clinical trials. Increased expression of geminin and higher geminin/MIB-1 ratios (increased speed of cycling) were associated with NPM1 mutations and improved response to induction therapy in both univariate and multivariate analysis. Patients with lower geminin/MIB-1 ratios had increased rates of relapse and, in a landmark analysis from the second cycle of treatment, a trend towards inferior overall survival. These results suggest a mechanism for the improved response and decreased relapse risk seen in patients with NPM1 mutations and the potential clinical utility of examining DNA replication licensing factors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available