JAK2 V617F: A Single Mutation in the Myeloproliferative Group of Disorders

The myeloproliferative disorders (MPD) are a group of haematological conditions where there is a primary disorder at the level of the multi-potent haematopoietic stem cell leading to increased production in one or more blood cell types. The three main disorders in the group are polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF). PV is characterised by an increase in red cells, white cells and platelets and clinically a plethoric appearance, itch and splenomegaly. The disease can be complicated by thromboembolic phenomena and haemorrhage and in the end stages can progress to myelofibrosis and acute leukaemia. ET is characterised by an increased platelet count. Clinically it is frequently asymptomatic but the thromboembolic events may lead to disease detection. There is a small propensity to progress to myelofibrosis and acute leukaemia which may be influenced by the treatment modalities used. IMF is defined by a leukoerythroblastic blood picture, splenomegaly and bone marrow fibrosis. The blood picture includes anaemia, thrombocythaemia or thrombocytopenia and variable white cell counts. The disease frequently progresses inexorably to transfusion dependent anaemia, symptomatic splenomegaly and transformation to acute leukaemia. A number of different biological phenomena have been described in haematopoietic cells from PV patients and other MPDs, the majority of which involve dysregulation of key signalling mediators. The key molecular events in the pathogenesis of these disorders have been poorly defined to date, except in the case of Chronic Myeloid Leukaemia (CML) with the associated characteristic chromosomal translocation 'the Philadelphia chromosome' and associated rearranged gene BCR – ABL. PV progenitor cells have been shown to grow in the absence of added erythropoietin, so called endogenous erythroid colony (EEC) formation 1 and to be hypersensitive to a variety of other cytokines including insulin-like growth factor-1. 2 EEC formation however is not specific to PV and is also identified in other MPDs. Other properties include increased expression of the inhibitor of apoptosis Bcl-x L in the absence of Epo in PV erythroid cells suggesting that deregulated expression of Bcl-xL may contribute to the erythropoietin dependent survival of erythroid lineage cells in PV. platelets and megakaryocytes from patients with PV has been shown to be reduced compared to normal controls. 4 This again is not specific to PV however and can occur in other MPDs. RNA synthesis from the polycythaemia rubra vera 1 (PRV-1) gene has been found to be over expressed in PV granulocytes. 5 Erythroid colonies from PV …