JAK2 (V617F) as an acquired somatic mutation and a secondary genetic event associated with disease progression in familial myeloproliferative disorders

BACKGROUND. A somatic gain-of-function mutation of the Janus kinase 2 (JAK2) gene has been identified in chronic myeloproliferative disorders, which appear to have a sporadic occurrence in most individuals. The authors studied the biologic significance of the JAK2 (V617F) mutation in familial myeloproliferative disorders. METHODS. Twenty pedigrees with familial chronic myeloproliferative disorders were identified through an investigation of family history in 264 patients with sporadic myeloproliferative disorders. A quantitative real-time polymerase chain reaction (qRT-PCR)-based allelic discrimination assay was employed for the detection of the V617F mutation in circulating granulocytes and T lymphocytes. An analysis of X-chromosome inactivation pattern was performed in female patients. RESULTS. Fourteen families had homogeneous phenotypes, and 6 families had mixed phenotypes. By using a qRT-PCR-based allelic discrimination assay, the JAK2 (V617F) mutation was detected in circulating granulocytes from 20 of 31 patients, but the mutation was not detected in T lymphocytes. Granulocyte mutant alleles ranged from 2.1% to 91.5% and, on average, increased with time. Discordant distribution of the JAK2 (V617F) mutation was observed in siblings with polycythemia vera. The proportion of granulocytes that carried the JAK2 (V617F) mutation was lower than the proportion of clonal granulocytes, as determined in an analysis of X-chromosome inactivation patterns in female patients. CONCLUSIONS. The current findings indicated that the JAK2 (V617F) mutation represents an acquired somatic mutation in patients with familial chronic myeloproliferative disorders and probably occurs as a secondary genetic event in the background of preexisting clonal hematopoiesis. Thus, a genetic predisposition to acquisition of JAK2 (V617F) is inherited in families with myeloproliferative disorders.