New Insights into the Molecular Pathogenesis of Bcr-Abl–Negative Myeloproliferative Disorders

Abstract The molecular pathogenesis of classic Philadelphia-negative myeloproliferative disorders (MPDs) has been greatly elucidated since the discovery of the JAK2V617F mutation in 2005. This abnormality is present in almost all patients with polycythemia vera and half of patients with essential thrombocythemia and primitive myelofibrosis. The mutation recapitulates many features of the human diseases in mouse models, is present in human hematopoietic stem cells, and is responsible for genomic instability. Nevertheless, many questions remain unanswered. How can 1 point mutation explain different disease phenotypes? Is JAK2V617F the sole event responsible for the JAK2V617F-positive MPDs? What is the cause of the disease in JAK2V617F-negative MPD? These questions are of particular interest at a time when different JAK2 inhibitors are being developed and used in clinical trials.