Identification of an Acquired JAK2 Mutation in Polycythemia Vera

TLDR

Polycythemia vera is a clonal hematologic disorder of unknown etiology, characterized by progenitor cells that are hypersensitive to growth factors, suggesting dysregulation of protein‑tyrosine kinases and phosphatases. The authors sequenced coding regions of candidate enzymes and identified a G:C→T:A point mutation in JAK2 in 20 of 24 PV samples, absent in normal controls. The acquired Val617Phe mutation in JAK2’s pseudokinase domain enhances kinase activity, hyperactivates erythropoietin signaling when co‑expressed with its receptor, and likely explains the growth‑factor hypersensitivity of PV progenitor cells, thereby defining a molecular defect of the disease.

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.