Although it has long been known that the myeloproliferative neoplasms (MPN) polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are clonal hematopoietic stem-cell disorders, for many years the genetic basis for these disorders was elusive. A new era in MPN biology began in 2005 with the discovery of a somatic point mutation in JAK2 tyrosine kinase (JAK2V617F), which was identified in a significant proportion of patients with PV, ET and PMF. Based on the hypothesis that JAK-STAT signaling is central to the pathogenesis of JAK2V617F-negative MPN, genomic studies have identified JAK2 exon 12 mutations in JAK2V617F-negative PV and activating mutations in MPL in patients with JAK2V617F-negative ET and PMF. In this review, we will discuss the role of these mutant alleles in the pathogenesis of PV, ET and PMF, the potential therapeutic implications of these discoveries, and the implications of these discoveries for genomic studies of hematopoietic malignancies.
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We acknowledge the patients, physicians, and investigators who have contributed to our understanding of these disorders. The Levine Laboratory is supported by the US National Institutes of Health, the Howard Hughes Medical Institute Early Career Award Program, the American Society of Hematology, and the Doris Duke Charitable Foundation Clinical Scientist Development Award program. RLL is an American Society of Hematology Basic Research Fellow and is the Geoffrey Beene Junior Chair at Memorial Sloan Kettering Cancer Center.
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Kilpivaara, O., Levine, R. JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. Leukemia 22, 1813–1817 (2008). https://doi.org/10.1038/leu.2008.229
- myeloproliferative neoplasms
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