A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
28 Apr 2005-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 352, Iss: 17, pp 1779-1790
TL;DR: Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages and a high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.
Abstract: background Polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are clonal myeloproliferative disorders arising from a multipotent progenitor. The loss of heterozygosity (LOH) on the short arm of chromosome 9 (9pLOH) in myeloproliferative disorders suggests that 9p harbors a mutation that contributes to the cause of clonal expansion of hematopoietic cells in these diseases. methods We performed microsatellite mapping of the 9pLOH region and DNA sequencing in 244 patients with myeloproliferative disorders (128 with polycythemia vera, 93 with essential thrombocythemia, and 23 with idiopathic myelofibrosis). results Microsatellite mapping identified a 9pLOH region that included the Janus kinase 2 ( JAK2 )
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TL;DR: The classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.
4,274 citations
Cites background or result from "A Gain-of-Function Mutation of JAK2..."
...It is recommended, however, that the cytogenetic abnormality be included in the diagnostic report, for example, “therapy-related AML with t(9;11)(p22;q23)....
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...Three new cytogenetically defined entities are added: (1) AML with t(6;9)(p23;q34); DEK-NUP214, (2) AML with inv(3)(q21q26....
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...1;q22), and APL with t(15; 17)(q22;q12) are considered as acute leukemia regardless of blast count in the PB or BM, but in contrast to the previous edition, for AML with t(9;11)(p22;q23) or other 11q23 abnormalities, as well as for all other subgroups (except the rare instance of some cases of erythroleukemia) blasts of 20% or more of white blood cells in PB or of all nucleated BM cells is required for the diagnosis of AML....
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...Mixed phenotype acute leukemia with t(9;22)(q34;q11....
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...B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11....
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TL;DR: Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death.
Abstract: Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. Methods We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Results Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow–biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Conclusions Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.)
2,497 citations
Cites background from "A Gain-of-Function Mutation of JAK2..."
...Busque L, Patel JP, Figueroa ME, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis....
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...Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers....
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...Three of these four genes — DNMT3A, TET2, and ASXL1 — also tend to harbor such mutations in hematologic cancers19-21 and are proposed to function as epigenetic regulators.22 Mutations in PPM1D, which functions as a regulator of tumor-suppressor protein p53,23 have been described more frequently in nonhematologic cancers....
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...Reflecting this relationship, participants having clonal hematopoiesis with candidate drivers were, on average, older than those without detectable putative somatic mutations (mean age, 64 years vs. 55 years; P<0.001); each of the most common driver genes (DNMT3A, ASXL1, TET2, PPMD1, and JAK2) also tended to have detectable somatic mutations in older persons (Fig....
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...Most cases of clonal hematopoiesis appeared to involve mutations in a specific subset of the genes recognized as drivers of blood cancers,22 such as DNMT3A, ASXL1, and TET2 (Fig....
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TL;DR: How cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts is described.
Abstract: Fibrosis is a key aspect of many chronic inflammatory diseases and can affect almost every tissue in the body. This review discusses recent advances in our understanding of the mechanisms of fibrosis, focusing on the innate and adaptive immune responses. It also describes how some of these crucial pathogenic pathways are being therapeutically targeted in the clinic.
2,492 citations
TL;DR: The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies.
Abstract: The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling
1,658 citations
TL;DR: Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR, and patients with mutated CALR had a lower risk ofThrombosis and longer overall survival than patients with mutations in J AK2.
Abstract: BACKGROUND Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients. METHODS We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms. RESULTS Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2. CONCLUSIONS Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.)
1,649 citations
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TL;DR: The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway transmits information received from extracellular polypeptide signals, through transmembrane receptors, directly to target gene promoters in the nucleus, providing a mechanism for transcriptional regulation without second messengers.
Abstract: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway transmits information received from extracellular polypeptide signals, through transmembrane receptors, directly to target gene promoters in the nucleus, providing a mechanism for transcriptional regulation without second messengers. Evolutionarily conserved in eukaryotic organisms from slime molds to humans, JAK-STAT signaling appears to be an early adaptation to facilitate intercellular communication that has co-evolved with myriad cellular signaling events. This co-evolution has given rise to highly adapted, ligand-specific signaling pathways that control gene expression. In addition, the JAK-STAT signaling pathways are regulated by a vast array of intrinsic and environmental stimuli, which can add plasticity to the response of a cell or tissue.
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TL;DR: Reconstitution experiments demonstrate that Jak2 is not required for the generation of lymphoid progenitors, their amplification, or functional differentiation, and plays a critical, nonredundant role in the function of a specific group of cytokines receptors.
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TL;DR: The data provided demonstrate that Jak2 has pivotal functions for signal transduction of a set of cytokine receptors required in definitive erythropoiesis.
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