The chronic myeloproliferative diseases, polycythemia vera (PV), essential thrombocythemia (ET), chronic idiopathic myelofibrosis (IMF), and chronic myelogenous leukemia (CML), were grouped into a spectrum of pathogenetically related disorders of varying clinical manifestations by Dameshek in 1951. 1 Recently, the World Health Organization has included the chronic eosinophilic leukemia/hypereosinophilic syndrome, chronic neutrophilic leukemia, and systemic mast cell disease (SMCD) within this grouping. Although the origin of CML has been traced to a dysregulated protein kinase, the product of the BCR/ABL oncogene, 2 and that of SMCD to 1 of 2 dysregulated receptor tyrosine kinases, c-kit, or the platelet-derived growth factor (PDGF) A receptor, 3 the molecular basis of the 3 classic disorders, PV, ET, and IMF, which as a group share more similarities with each other than with CML, has been more recalcitrant to solution. However, a major insight into the molecular basis for the enhanced myeloproliferation and clonal dominance that characterizes these disorders has now been reported; the answer is another kinase, and, best of all, it all makes sense! In recent issues of the Lancet, 4 Cancer Cell, 5 Nature, 6 and the New England Journal of Medicine, 45 a single, somatic mutation in the protein tyrosine kinase Janus kinase 2 (JAK2) appears responsible for many of the features of PV, ET, and IMF, a finding that promises to impact the diagnosis and treatment of patients with these disorders and to spur additional research into the origins of dysregulated cell growth and function. The chronic myeloproliferative disorders share many features: the marrow is hypercellular and overproduces one or more of the formed elements of the blood in the absence of any apparent appropriate or pathologic stimulus; the exuberant hematopoiesis often also extends to one or more extramedullary sites. Based on studies using polymorphic genes, these disorders were shown to be clonal, 7 thought to arise in a single, multipotent hematopoietic progenitor or stem cell, which comes to dominate the marrow and blood. Hematopoietic progenitor cells from the marrow or peripheral blood display altered growth properties, proliferating in serum containing cultures in the absence of exogenous hematopoietic growth factors. 8 Marrow megakaryocytes are hyperplastic and variably dysplasia and are responsible for the myelofibrosis of these disorders, patients often display a tendency toward thrombotic and hemorrhagic complications in addition to their signs and symptoms related to expansion of each hematopoietic lineage. However, compared with patients with CML, transformation to acute leukemia is far less common, especially in the absence of therapy with known mutagenic agents. But despite these clinical and pathologic features, the diagnosis of an individual patient with isolated erythrocytosis or thrombocytosis is often difficult, and their treatment is usually a nonspecific suppression of hematopoiesis.

Although consistent chromosomal rearrangements have been the vital roadmap pointing investigators toward the molecular pathogenesis of CML and multiple types of acute myelogenous and lymphoid leukemia, these same clues have been neither abundant nor particularly informative in the study of chronic myeloproliferative disorders; without such signs, progress in understanding PV, ET, and IMF has been slow. Nevertheless, some successes have been reported. Instances of inherited, isolated erythrocytosis and pure thrombocytosis have been solved, traced to the loss of a negative regulatory domain of the erythropoietin (EPO) receptor, 9 to an abnormality in an …