JAK inhibitors in myeloproliferative neoplasms

27 Introduction The Janus kinases (JAKs) are a family of 4 nonreceptor tyrosine kinases that play an essential role in mediating cytokine signalling. JAKs associate with cytokine receptors that lack intrinsic kinase activity to mediate cytokine-induced signal transduction via the activation of the STAT transcription factors and other signalling pathways (Figure 1, page 28).1,2 The 4 family members (JAK1, 2, 3 and TYK2) associate with different cytokine receptors (Table 1, page 29). The possible involvement of JAK dysregulation in oncogenesis was suggested by a mutation in the Drosophila JAK kinase, hopscotch, which was inducing leukaemia in the fly.3 In 2005, several studies demonstrated that a unique acquired activating somatic mutation of JAK2 (V617F) was found in 95% of polycythaemia vera (PV) patients and in about half of essential thrombocythaemia (ET) and primary myelofibrosis (PMF) patients.4-7 Mutations of the homologous V617F residue in JAK1 and TYK2 were shown to activate those Janus kinases.8 This and other mutations of JAK1 were subsequently described in acute lymphoblastic leukaemia and activating mutations of JAK3 were detected in a megakaryoblastic leukaemia cell line.9-11 Based on the excellent results obtained