Molecular Biology

The marked prevalence of the mutation V617F in JAK2 kinase in PV (85-95%)3-7 implies that it is most likely to be involved in the pathogenesis of this condition.

V617F JAK2 positive MPD

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2o hits e.g. V617F JAK2; MPLW515L/K

Figure 46.2 Proposed scheme for molecular pathogenesis and classification of chronic MPDs. A primary hit or hits affect a hematopoietic stem cell and may cause a "pre-MPD stem cell." Second hits are likely to include V617FJAK2 and MPLW515L/K and other as yet unidentified mutations. A continuum through ET to advanced disease is proposed where a potential drive to progression is load of V617F JAK2 due to mitotic recombination and clonal dominance but is likely to also include other genetic events.

2o hits e.g. V617F JAK2; MPLW515L/K

617F JAK2 negative MPD

Figure 46.2 Proposed scheme for molecular pathogenesis and classification of chronic MPDs. A primary hit or hits affect a hematopoietic stem cell and may cause a "pre-MPD stem cell." Second hits are likely to include V617FJAK2 and MPLW515L/K and other as yet unidentified mutations. A continuum through ET to advanced disease is proposed where a potential drive to progression is load of V617F JAK2 due to mitotic recombination and clonal dominance but is likely to also include other genetic events.

This is also supported by transplantation studies in mice who rapidly develop the phenotype of PV and later also develop fibrosis.4 Here a single point mutation converts a highly conserved valine to a bulky phenylalanine which is thought to stoichiometrically affect the interaction between the kinase and pseudokinase domains of JAK2 (reviewed in Refs. 16 and 17). Studies4-6 have shown that the JAK2 mutation causes cytokine independent activation of JAKSTAT, P13K-AKT and ERK pathways, these are involved in erythropoeitin receptor signaling. The current status of knowledge in relation to the role of Janus kinases in hemopoiesis and hematological malignancy has recently been reviewed.16 This mutation potentially explains many of the features previously reported in PV including hypersensitivity to a number of other cytokines, granulocyte-macrophage colony-stimulating factor, stem cell factor, inter-leukin-3 and insulin-like growth factor 1, and reduced expression of cMPL.18 In addition to the constitutive activity of STAT3 reported in a proportion of PV patients,19 the mRNA for polycythemia rubra vera 1 (PRV-1) is elevated in granulocytes of PV patients20; overexpression of PRV-1 correlates strongly with endogenous colony formation in PV, ET, and MF2122 and also with V617F.23

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