Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders

An acquired gain-of-function mutation in the Janus kinase 2 (JAK2V617F) is frequently found in patients with myeloproliferative disorders (MPDs). To test the hypothesis that JAK2-V617F is the disease-initiating mutation, we examined whether all cells of clonal origin carry the JAK2-V617F mutation. Using allele-specific polymerase chain reaction (PCR) assays for the JAK2 mutation and for the X-chromosomal clonality markers IDS and MPP1, we found that the percentage of granulocytes and platelets with JAK2V617F was often markedly lower than the percentage of clonal granulocytes determined by IDS or MPP1 clonality assays in female patients. Using deletions of chromosome 20q (de120q) as an autosomal, X-chromosome-independent clonality marker, we found a similar discrepancy between the percentage of cells carrying JAK2-V617F and de120q. Our results suggest that in a proportion of patients with MPDs, JAK2-V617F occurs on the background of clonal hematopoiesis caused by a somatic mutation in an as-yet-unknown gene.