Molecular Biology

ET is a clinically heterogeneous disorder which is reflected in molecular analyses in these patients. Indeed a significant proportion of ET patients do not have clonal hemopoiesis as assessed using X-chromo-some inactivation patterns and this subgroup may be at a lower risk of thrombotic complications.2829 These findings may also reflect technical limitations or a low disease burden undetectable against a polyclonal background.

The V617F JAK2 mutation is detected in 50% of patients with ET3,30,31 and painstaking analysis of progenitors suggests that in ET it is highly unusual to detected homozygosity for V617F JAK2.32 The majority of ET patients negative for V617F JAK2 mutation have features characteristic of an MPD.33 The V617F positive ET patients share features in common with PV patients including higher hemoglobins and white cell counts30,34 but have features that constrain erythro-poiesis such as low erythropoietin levels and iron stores.34 A small proportion of ET patients appear to have one of two mutations in cMPL in the juxtamem-brane domain of the intracytoplasmic tail9,35 in mouse models this recapitulates the clinical features of ET and MF.9

Most patients with V617F JAK2 negative ET or MF will continue to be V617F JAK2 negative as suggested by most published data thus far36,37; potential candidates for molecular aetiology in V617F JAK2 negative ET are manifold.

There is an emerging evidence for a V617F JAK2 negative subclinical pre-MPD phase most powerful of which is that in patients previously noted to be V617F JAK2 positive when a leukemic clone emerges it is frequently V617F negative.36 An alternative explanation for V617F JAK2 negative leukemia occurring in these patients is that V617F JAK2 must be lost to induce a block upon differentiation; however, experiments to investigate loss of heterozygosity in the appropriate chromosomal region suggest this is not the case. Most of these patients had received hydroxyurea alone not multiple therapies so transformation of a normal stem cell seemed improbable. Further data suggesting a disparity between size populations of clonal myeloid cells (as judged by X-chromosome inactiva-tion patterns) and V617JAK2 positive cells also suggests a pre-V617F clone3839; where clonality is judged by loss of heterozygosity at 20q this data is most con-vincing38 as there are significant problems in interpreting clonality using XCIPs in V617F JAK2 positive disease.36

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