76 American Society of Hematology New Advances in the Pathogenesis and Therapy of Essential Thrombocythemia Ross L. Levine 1,2 and Mark Heaney 2 1 Human Oncology and Pathogenesis Program; 2 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY Essential thrombocythemia (ET) is a hematopoietic disorder that manifests clinically as thrombocytosis, and patients with ET are at increased risk for develop- ing thrombosis, myelofibrosis, and transformation to acute myeloid leukemia. Although ET was recognized as a distinct clinical syndrome more than 6 decades ago and was classified as a myeloproliferative neoplasm (MPN) by William Dameshek in 1951, the molecular pathogenesis of ET remained unknown until 2005, when activating mutations in the JAK2 tyrosine kinase (JAK2V617F) were identified in a significant proportion of patients with ET, polycythemia vera (PV) and primary myelofibrosis (PMF). In addition, subse- quent studies have identified gain-of-function muta- tions in the thrombopoietin receptor (MPL) in a subset of patients with JAK2V617F-negative ET, suggesting that JAK2 activation by distinct mechanisms contrib- utes to the pathogenesis of ET. Despite these impor- tant observations, important questions remain regarding the role of JAK2/MPL mutations in ET pathogenesis, the etiology of JAK2/MPL negative ET, the factors that distinguish ET from other MPNs with the JAK2V617F mutation, and the role of JAK2- targeted therapies for the treatment of these MPNs. Essential Thrombocythemia: Description and Classification Essential thrombocythemia (ET) is a myeloid disorder that is characterized by an increase in the peripheral blood plate- let count that is associated with bone marrow megakaryo- cyte hyperplasia, without associated erythrocytosis or leukoerythroblastosis. 1 ET was first recognized as a dis- tinct clinical syndrome by Emil Epstein and Alfred Godel in 1934, 2 and subsequently was recognized as one of the classic myeloproliferative neoplasms (MPN) based on the classification delineated by William Dameshek, the found- ing editor of Blood, in his seminal editorial in 1951. 3 Prior to the identification of JAK2V617F mutations in a signifi- cant proportion of patients with polycythemia vera (PV), ET, and primary myelofibrosis (PMF), 4-8 a diagnosis of ET required thrombocytosis (platelet count of at least 600 × 10 9 /mL) and megakaryocyte hyperplasia without clinical, pathologic, or molecular evidence supporting a diagnosis of PV, PMF, chronic myeloid leukemia (CML), myelodys- plasia (MDS), or reactive thrombocytosis. 9 Although the discovery of JAK2V617F is an important advance in our understanding of the molecular pathogenesis of ET (see below), the presence of the JAK2V617F allele in more than one MPN and the absence of the JAK2V617F allele in many patients with ET preclude the use of JAK2V617F testing alone to establish a diagnosis of ET. This is reflected in the revised WHO diagnostic criteria for ET, which lowered the platelet threshold for a diagnosis of ET to 450 × 10 9 /mL, and allows JAK2V617F testing to demonstrate the pres- ence of a clonal MPN, but still requires clinicians to ex- clude a diagnosis of PV, PMF, CML, or MPN based on clini- cal, laboratory, and pathologic data. 10 It is important to note, however, that it is difficult to consistently apply patho- logic criteria to distinguish ET from the other MPN and that it is difficult to distinguish between ET and the prefibrotic/cellular phase of PMF based on clinical, labo- ratory, or morphologic features. 11 JAK2V617F Mutations in ET Although clonality studies, initially performed through analysis of G6PD isoforms in informative females 12 and later through analysis of X-inactivation using PCR-based assays, 13,14 demonstrated that PV, ET, and PMF are clonal disorders that originate in multipotent hematopoietic pro- genitors, the molecular pathogenesis of these MPNs re- mained an enigma until a series of studies identified the JAK2V617F mutation in PV, ET and PMF. 4-8 These studies demonstrated that the guanine to thymine transversion that leads to a valine to phenylalanine substitution at codon 617 is acquired as a somatic mutation in the hematopoietic compartment. To date, this allele has not been identified in the germline of any patients with MPN, even in kindreds with a familial proclivity for the development of ET and other MPN. 15 The absence of germline mutations in JAK2 is, perhaps, not surprising given the importance of JAK2 function to a wide spectrum of cellular functions 16 that pre- sumably would be altered by heritable gain-of-function JAK2 mutations. Subsequent to the identification of the JAK2V617F allele, sensitive, allele-specific assays including BsaXI di- MYELOPROLIFERATIVE DISORDERS _______________________________________________________________