Identification of an Acquired JAK2 Mutation in Polycythemia Vera

• Published in: The Journal of biological chemistry 2005-06, Vol.280 (24), p.22788-22792
• Main Authors: Zhao, Runxiang, Xing, Shu, Li, Zhe, Fu, Xueqi, Li, Qingshan, Krantz, Sanford B, Zhao, Zhizhuang Joe
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Cytokines - metabolism; DNA Mutational Analysis; DNA, Complementary - metabolism; Erythropoietin - metabolism; HeLa Cells; Heterozygote; Humans; Immunoblotting; Janus Kinase 2; Molecular Sequence Data; Mutation; Phenylalanine - chemistry; Point Mutation; Polycythemia Vera - genetics; Polymerase Chain Reaction; Protein Structure, Tertiary; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Receptors, Erythropoietin - chemistry; Receptors, Erythropoietin - metabolism; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Signal Transduction; Transfection; Tyrosine - chemistry; Valine - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C500138200

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.