William Vainchenker had long suspected a rogue JAK2 tyrosine kinase to be the cause of the myeloproliferative disorder, polycythemia vera. But with very limited resources at his disposal at the Gustave Roussy Institute in Paris, he could not afford large-scale sequencing efforts. Working with only three patients, his team concentrated on tracking down JAK2 gene mutations. "We were lucky," says Vainchenker. "We found the same mutation in two of them."
The culprit turned out to be a single nucleotide mutation at codon 617, changing valine to phenylalanine in JAK2's autoinhibitory domain. "Finding the mutation was the hard part," said Vainchenker. "The rest was pretty straightforward." The team went on to show that the V617F mutation produced a constitutive JAK2 activation in erythroid progenitor cells, causing spontaneous STAT-mediated transcription even in the absence of erythropoietin. They also demonstrated that mice transfected with V617F developed eythrocytosis, the characteristic symptom of polycythemia vera. ...
