Identification of an Acquired JAK2 Mutation in Polycythemia Vera

Runxiang Zhao,Shu Xing,Zhe Li,Xueqi Fu,Qingshan Li,Sanford B Krantz,Zhizhuang Joe Zhao

doi:10.1074/jbc.c500138200

Runxiang Zhao, Shu Xing + Show 5 more

Open Access

https://doi.org/10.1074/jbc.c500138200

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Abstract

Polycythemia vera (PV) is a human clonal hematological disorder. The molecular etiology of the disease has not been identified. PV hematopoietic progenitor cells exhibit hypersensitivity to growth factors and cytokines, suggesting possible abnormalities in protein-tyrosine kinases and phosphatases. By sequencing the entire coding regions of cDNAs of candidate enzymes, we identified a G:C--> T:A point mutation of the JAK2 tyrosine kinase in 20 of 24 PV blood samples but none in 12 normal samples. The mutation has varying degrees of heterozygosity and is apparently acquired. It changes conserved Val(617) to Phe in the pseudokinase domain of JAK2 that is known to have an inhibitory role. The mutant JAK2 has enhanced kinase activity, and when overexpressed together with the erythropoietin receptor in cells, it caused hyperactivation of erythropoietin-induced cell signaling. This gain-of-function mutation of JAK may explain the hypersensitivity of PV progenitor cells to growth factors and cytokines. Our study thus defines a molecular defect of PV.

Highlights

Polycythemia vera (PV)1 is a clonal myeloproliferative disorder characterized by increased production of red cells, granulocytes, and platelets [1,2,3]
Identification of a JAK2 Mutation in PV—Initially, we hypothesized that PV might be caused by mutations of protein-tyrosine kinases (PTKs) and/or PTPs
The mutation is apparently not confined to erythroid progenitor cells, because no increase in the portion of mutant JAK2 was seen with RNAs isolated from purified erythroid colonyforming cells, reflecting the multiple lineage feature of PV

Summary

Introduction

Polycythemia vera (PV)1 is a clonal myeloproliferative disorder characterized by increased production of red cells, granulocytes, and platelets [1,2,3]. By sequencing the entire coding regions of cDNAs of candidate enzymes, we identified a G:C3 T:A point mutation of the JAK2 tyrosine kinase in 20 of 24 PV blood samples but none in 12 normal samples. The mutant JAK2 has enhanced kinase activity, and when overexpressed together with the erythropoietin receptor in cells, it caused hyperactivation of erythropoietin-induced cell signaling.

Results

Conclusion