On the Molecular Origins of the Chronic Myeloproliferative Disorders: It All Makes Sense

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 inhibitory regulator (von Hippel Lindau protein) of the key transcription factor for EPO, hypoxia inducible factor 1 ,10 to abnormal splicing of thrombopoietin (TPO) mRNA resulting in enhanced translational efficiency and high levels of the primary humoral regulator of platelet production,11 or to 2 separate point mutations in the TPO receptor, c-Mpl.12,13 Nevertheless, none of these clinical instances are characterized by the clonal, pan-myeloid myeloproliferation that characterizes patients with chronic myeloproliferative disorders. One of the most intriguing characteristics of PV has been endogenous erythroid colony (EEC) formation, in which erythroid progenitor cells obtained from the marrow or peripheral blood proliferate in semisolid, serum-containing cultures in the absence of exogenous EPO. Although initially described for patients with PV,8 similar results can be demonstrated in a significant proportion of patients with ET and IMF, but never in healthy individuals. Thus, EEC formation has become a relatively useful, albeit cumbersome diagnostic test for myeloproliferative disorders. Unfortunately, the assay is technically demanding and is positive in only about 35% to 80% of patients with these diseases. Although initially believed to represent “EPO-independent” growth, subsequent studies revealed the phenomenon of EEC to represent hypersensitivity to the EPO present in the serum used in the cultures.14 These findings suggested that abnormalities of the EPO receptor might underlie PV. Unfortunately, except for the description of familial erythrocytosis noted earlier, the EPO receptor has been found to be completely normal in all patients with bona fide PV.15 Moreover, subsequent studies revealed that marrow and blood cells from patients with PV were hypersensitive not only to EPO but also to several other hematopoietic growth factors, including interleukin 3 (IL-3), stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GMCSF), insulin-like growth factor-1 (IGF-1), and TPO.16-19 These findings suggested that events downstream from receptor engagement might be responsible for EEC formation. Protein tyrosine phosphorylation is vital for transduction of growthpromoting signals for a wide range of cellular mitogens. However, with the cloning of the EPO receptor in 1989,20 a conundrum emerged; unlike the receptors for well-characterized mitogens such as epidermal growth