JAK2V167F Mutations in Polycythemia Vera

JAK2V167F Mutations in Polycythemia Vera

Introduction

Janus kinase 2 (JAK2) is a cytoplasmic tyrosine kinase that transduces signals, especially those triggered by hematopoietic growth factors such as erythropoietin, in normal and neoplastic cells. In March and April 2005, four groups of investigators reported finding an acquired JAK2 mutation (termed JAK2 V617F) in association with polycythemia vera and related myeloproliferative disorders.

The acquired Janus kinase 2 (JAK2) V617F mutation shows a high frequency in diverse BCR/ABL-negative chronic myeloproliferative disorders (CMPD), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). A guanine-to-thymidine substitution at nucleotide position 1849 leads to a valine to phenylalanine exchange at amino acid position 617, which is localized in pseudo-kinase JAK homology-2 (JH2) domain of the exon 12(Baxter.et.al, 2005) . The JAK2 gene encodes a cytoplasmic tyrosine kinase. The JAK2 V617F mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis and subsequent myelofibrosis in a mouse model and , suggesting a causal role in CMPD. In this report6 mutation in Polycythemia Vera will be explained by giving example of a case study so that concepts can be further clarified .

Discussion

Literature Review

The frequency of the JAK2 V617F mutation is about 90% in patients with PV, 50-60% in patients with ET and PMF, and less in other myeloid neoplasms whereas it is extremely rare in lymphoid malignancies (Baxter.et.al, 2005). Homozygosity for the V617F mutation commonly occurs in patients with PV, but is rare in patients with ET, suggesting that it may be associated with a polycythemic phenotype (Karow.et.al 2008).

Normally, JAK2 activation involves tightly regulated cytokine-induced phosphorylation of tyrosine residues in the kinase and negative regulatory JAK homology domains — JH1 and JH2, respectively. JAK2 V617F, resulting from a point mutation (1849G->T) in exon 14, causes the substitution of phenylalanine for valine at codon 617 in the JH2 domain. This change in a single amino acid renders the JAK2 enzyme constitutively active(Baxter.et.al, 2005). The four JAK2 mutations described by Scott et al. are in-frame deletions or tandem point mutations in exon 12. Both JAK2 V617F and the exon 12 JAK2 mutations induce cytokine-independent proliferation of cell lines that express erythropoietin receptors and cause these cells to become hypersensitive to cytokines. Moreover, the transfection of hematopoietic stem cells with a mutant JAK2 gene causes a polycythemia vera-like phenotype in mice (Scott.et.al, 2006).

These observations implicate JAK2 mutations as essential elements in the development of polycythemia vera. Whereas the exon 12 JAK2 mutations seem specific for polycythemia vera and idiopathic erythrocytosis, the exon 14 JAK2 V617F mutation occurs not only in polycythemia vera, but also in essential thrombocythemia and primary myelofibrosis (Horn .et.al 2006). Often, only one allele carries the JAK2 mutation, but the loss of heterozygosity through mitotic recombination converts the affected cell from a heterozygous to a homozygous carrier of the mutation. This event occurs most frequently in polycythemia vera. Homozygosity endows the cell with a proliferative advantage, and the increase in the allele burden probably contributes to full expression of the polycythemia vera ...