JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science

• Published in: Leukemia Vol. 22; no. 10; pp. 1813 - 1817
• Main Authors: Kilpivaara, O, Levine, R L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2008; Nature Publishing; Nature Publishing Group
• Subjects: Biological and medical sciences; Blood cancer; Cancer; Cancer Research; Cellular signal transduction; Critical Care Medicine; Cytokines; Disorders; Gene Dosage; Gene mutations; Genes; Genetic aspects; Genetic Predisposition to Disease; Genomics; Health aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Intensive; Internal Medicine; Janus kinase 2; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - genetics; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mutation; Myelofibrosis; Myeloproliferative disorders; Neoplasms; Oncology; Pathogenesis; Point mutation; Polycythemia; Polycythemia vera; Polycythemia Vera - genetics; Primary Myelofibrosis - genetics; Protein-tyrosine kinase; Receptors, Thrombopoietin - genetics; Risk factors; spotlight-review; Stem cells; Thrombocythemia, Essential - genetics; Tumors; Tyrosine; United States; New York; United States > US; myeloproliferative neoplasms; MPL; JAK2; Thrombopoietin receptor; Hematology; Enzyme; JAK2 protein tyrosine kinase; Transferases; Hemopathy; Myeloproliferative syndrome; Growth factor receptor; C-Onc gene; Genetics; Mutation; Protein-tyrosine kinase; Protooncogene
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2008.229

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.