Lambert, J.R.; (2011) Investigations into the molecular pathogenesis of essential thrombocythaemia. Doctoral thesis , UCL (University College London).

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Abstract

In order to explore the phenotypic heterogeneity of the myeloproliferative neoplasm essential thrombocythaemia (ET), the role of the JAK2 mutation V617F in the pathogenesis of the disease was investigated, in particular its relationship to myeloid clonality. The clinical, haematological and molecular characteristics of 133 ET patients were studied. JAK2 V617F was detected in 55 (41%) patients; a clonal X-chromosome inactivation pattern (XCIP) was found in 24 (39%) of the 62 evaluable female patients. There was no association between JAK2 mutational status and XCIP status or thrombotic risk, but higher JAK2 V617F mutant levels were noted in patients who had a thrombosis. A trend towards a higher thrombotic rate was observed in patients whose XCIP was clonal. In 10 untreated JAK2 V617F-positive ET patients, JAK2 WT thrombopoiesis was not suppressed despite the presence of a thrombocytosis, suggesting that the regulation of JAK2 WT thrombopoiesis was abnormal. Eleven patients were screened for the presence of more than one JAK2 V617F-positive population using an exonic SNP located near the mutation. In ten (91%) of these the mutation appeared to have been independently acquired on at least two occasions. Furthermore, XCIP analysis of JAK2 V617Fpositive erythroid colonies from six ET patients revealed that in one patient the V617F-positive populations were not derived from a single clonal population. An association between the reported JAK2 haplotype (known as ‘46/1’) and JAK2 V617F-positive ET patients was observed in the cohort studied. Methylation studies indicated that this haplotype introduced additional methylated sites near to the mutation locus, which may potentially affect conformation of the DNA and mutability of the JAK2 locus. Together, the studies reported in this thesis suggest that JAK2 V617F is not the initiating event at least in some cases of ET, and that its presence does not invariably indicate the presence of a monoclonal disorder.

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