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Title: The molecular pathogenesis and management of the myeloproliferative disorders
Author: Campbell, P. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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The myeloproliferative disorders (MPDs) are clonal haematological malignancies comprising three main entities: polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF). The disorders are characterised by overactive haematopoiesis with a propensity to thrombosis, haemorrhage and leukaemic transformation. One chapter of this thesis covers the PT-1 trial, the largest randomised clinical trial in the MPDs. Patients with ET at high risk of thrombosis were randomised between hydroxyurea + aspirin and anagrelide + aspirin. The primary end-point of arterial or venous thrombosis, major haemorrhage or vascular death was increased in the anagrelide arm. The three secondary end-points of arterial thrombosis, major haemorrhage and myelofibrotic transformation were more common in the anagrelide arm, whereas venous thrombosis was more frequent in patients on hydroxyurea. Three chapters cover the molecular pathogenesis of the MPDs. Firstly, two balanced chromosomal translocations in patients with ET are characterised. The breakpoints of a t(X;5) translocation were shown to lie close to the X inactivation centre on the X chromosome and the common deleted region for the 5q-syndrome on chromosome 5. The inactive X chromosome was translocated, leading to monoallelic expression of genes in the 5q-region. This suggests spread of X inactivation as a novel mechanism of oncogenesis. A t(1;22) translocation was also characterised and shown to lead to synthesis of a Rho guanine nucleotide exchange factor with aberrant N terminus. The other two chapters describe the JAK2 V617F mutation. With an appropriately sensitive method for its detection, the mutation is found in virtually all patients with PV, and about half those with ET and IMF, 776 DNA samples from patients in the PT-1 trials were tested for the mutation, and clinical and laboratory findings compared. Compared to those without the mutation, V617F-positive patients with ET had higher haemoglobin levels and white cell counts, greater marrow cellularity, more venous thromboses, greater sensitivity to hydroxyurea (but not anagrelide) and lower erythropoietin levels and iron stores.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available