New advances in the pathogenesis and therapy of essential thrombocythemia.
Essential thrombocythemia (ET) is a hematopoietic disorder that manifests clinically as thrombocytosis, and patients with ET are at increased risk for developing 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, subsequent studies have identified gain-of-function mutations in the thrombopoietin receptor (MPL) in a subset of patients with JAK2V617F-negative ET, suggesting that JAK2 activation by distinct mechanisms contributes to the pathogenesis of ET. Despite these important 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.
Levine
Ross L
RL
Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. leviner@mskcc.org
Heaney
Mark
M
D019943:Amino Acid Substitution; D001792:Blood Platelets / Q000201:enzymology; D002899:Chromosomes, Human, Pair 9; D003062:Codon / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006098:Granulocytes / Q000201:enzymology; D006720:Homozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000628:therapy*; D009154:Mutation; D053628:Receptors, Thrombopoietin / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000628:therapy*; D013922:Thrombocytosis / Q000209:etiology / Q000628:therapy; D034061:Thrombopoiesis / Q000235:genetics; D024182:Uniparental Disomy / Q000235:genetics
D003062:Codon; D053628:Receptors, Thrombopoietin; D005954:Glucosephosphate Dehydrogenase; C507924:JAK2 protein, human; D053614:Janus Kinase 2