Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7.
Ontology highlight
ABSTRACT:
SUBMITTER: Frohling S
PROVIDER: S-EPMC1895918 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:We present cell line SET-2 as potential model system for DNA methylation analysis. This cell line was established from a patient with essential thrombocythemia at megakaryoblastic transformation and carries the JAK2 V617F mutation. Cell line SET-2 carries the DNMT3A R882H mutation, recurrent in cytogenetically normal AML.
2019-11-13 | E-MTAB-8323 | biostudies-arrayexpress
Project description:ObjectiveAdrenal incidentaloma are lesions which are stated incidentally by imaging methods when there is no suspicion of any disease in adrenal gland. Inappropriate Jak2 signaling causes some solid and hematological malignancies. But the Jak2 mutation has not been previously evaluated with regard to adrenal tumors. In this study, we aimed to positivity of the Jak2 mutation in patients with non functioning adrenal incidentaloma (NFAI).Methods45 (38 female-7 male) patients, who were followed due to NFAI at Tepecik Training and Research Hospital, Department of Endocrinology and Internal Medicine between February 2014 and March 2015, and 45 (31 female-14 male) healthy controls were included in the study.ResultsThe average age was 54.02±11.7 years and 38 patients were female, 7 were men. All patients underwent the following analyses for excluding a functioning adrenal mass, overnight dexamethasone suppression test, 24 hour urinary metanephrine and normetanephrine, plasma aldosterone/ renin activity ratio. Jak2 mutation of the patients who were diagnosed as NFAI was all negative.ConclusionWe could not identify the JAK2 gene mutation positivity in any sample. Since other possible mechanisms may throw fresh light on the etiology of adrenal incidentaloma, further clinical studies are needed on this subject.
| S-EPMC6516447 | biostudies-literature
Project description:A point mutation in the JAK2 gene, a member of the tyrosine kinase family, was recently identified and shown to be associated with several myeloproliferative disorders. Several studies identified the same JAK2 point mutation (1,849G>T), resulting in the substitution of a valine to phenylalanine at codon 617 (V617F). We developed a simple and sensitive method to detect this mutation via polymerase chain reaction and probe dissociation analysis using the LightCycler platform, and we compared this method to existing restriction fragment-length polymorphism, direct sequencing, and amplification refractory mutation system methods. We found that the LightCycler method offered advantages of speed, reliability, and more straightforward interpretation over the restriction fragment-length polymorphism and sequencing approaches.
| S-EPMC1867612 | biostudies-literature
Project description:The discovery of a single point mutation in the JAK2 gene in patients with BCR/ABL-negative myeloproliferative neoplasms (MPNs) has not only brought new insights and pathogenesis, but also has made the diagnosis of MPNs much easier. Although, to date, several mechanisms for the contribution of single JAK2V617F point mutation to phenotypic diversity of MPNs have been suggested in multiple studies, but it is not clear how a unique mutation can cause the phenotypic diversity of MPNs. In this study, our results show that allelic expression imbalance of JAK2 V617F mutant frequently occurs and contributes to phenotypic diversity of BCR-ABL-negative MPNs. The proportion of JAK2 V617F mutant allele was significantly augmented in RNA levels as compared with genomic DNA differently by distinct MPNs subtypes. In detail, preferential expression of JAK2 mutant allele showed threefold increase from the cDNA compared with the genomic DNA from patients with essential thrombocythemia and twofold increase in polycythemia vera. In conclusion, allelic expression imbalance of JAK2 V617F mutant proposes another plausible mechanism for the contribution of single JAK2 point mutation to phenotypic diversity of MPNs.
| S-EPMC3551963 | biostudies-literature
Project description:Portal vein thrombosis is an uncommon finding that typically arises in the context of cirrhosis. In the acute setting, it may present with abdominal pain, portal hypertension, ascites, gastrointestinal bleeding, or mesenteric ischemia. Local risk factors that predispose its formation include: cirrhosis, hepatocellular carcinoma, pancreatitis, and intraabdominal infection. Systemic factors, including hypercoagulable states and sepsis, also pose an increased risk. JAK2 V617F positive myeloproliferative disorders are associated with systemic prothrombotic states and are a less frequently identified cause of portal vein thrombosis. We present a case of acute unprovoked portal vein thrombosis diagnosed in a 59-year-old male without local disease factors. Computed tomography, magnetic resonance cholangiopancreatography, and ultrasound demonstrated the presence of portal vein thrombosis with neighboring periportal and pancreatic head edema. Peripheral blood testing detected the presence of JAK2 V617F mutation. The patient was discharged on 6-month anticoagulation therapy and outpatient follow-up.
| S-EPMC6148830 | biostudies-other
Project description:Familial essential thrombocythemia features the acquisition of somatic mutations and an evolution similar to the sporadic form of the disease. Here we report two patients-father and daughter-with essential thrombocythemia who displayed a heterogeneous pattern of somatic mutations. The JAK2 V617F mutation was found in the daughter, while the father harbored the MPL W515L mutation. This case report may constitute further proof that in familial essential thrombocythemia there are other, still undefined, constitutional, inherited genetic factors predisposing to the acquisition of various somatic mutations (e.g., JAK2 V617F and MPL).
| S-EPMC4267161 | biostudies-literature
Project description: Not available
| S-EPMC8448748 | biostudies-literature
Project description:The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F-positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2(V617F) mice develop reduced numbers of lineage(-)Sca-1(+)c-Kit(+) cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2(V617F) mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.
| S-EPMC3145111 | biostudies-literature
Project description:JAK2 (Janus tyrosine kinase 2) is important for signalling through many cytokine receptors, and a gain-of-function JAK2 mutation in its pseudokinase domain, V617F, has been implicated in Philadelphia chromosome-negative myeloproliferative neoplasms. How this mutation hyperactivates JAK2 is poorly understood. In the present paper we report our findings that the V617F mutation has little effect on the Vmax of JAK2 kinase activity, but lowers the Km value for substrates. Therefore under physiological conditions where the concentration level of substrates is presumably below saturation, JAK2(V617F) exhibits hyperactivation compared with wild-type JAK2. This lower Km of JAK2(V617F) towards substrates requires the JAK2 FERM (4.1/ezrin/radixin/moesin) domain, as deletion of the FERM domain abolished this effect. We also show that, in contrast with its positive role in JAK2(V617F) hyperactivation, the FERM domain in wild-type JAK2 is inhibitory. Deletion or mutations of the FERM domain resulted in increased basal JAK2 kinase activity. The results of the present study provide the biochemical basis for how V617F hyperactivates JAK2, and identifies novel regulating roles of the JAK2 FERM domain to control kinase activity at different activation states.
| S-EPMC8514084 | biostudies-literature
Project description:JAK2-V617F plays a key role in the pathogenesis of myeloproliferative neoplasm. However, its inhibitor ruxolitinib has shown limited clinical efficacies because of the ruxolitinib-persistent proliferation of JAK2-V617F-positive cells. We here demonstrate that the USP9X inhibitor WP1130 or EOAI3402143 (G9) inhibited proliferation and induced apoptosis more efficiently in cells dependent on JAK2-V617F than on cytokine-activated JAK2. WP1130 preferentially downregulated activated and autophosphorylated JAK2-V617F by enhancing its K63-linked polyubiquitination and inducing its aggresomal translocation to block downstream signaling. Furthermore, JAK2-V617F associated physically with USP9X in leukemic HEL cells. Induction of apoptosis by inhibition of USP9X was mediated through the intrinsic mitochondria-mediated pathway, synergistically enhanced by BH3 mimetics, prevented by overexpression of Bcl-xL, and required oxidative stress to activate stress-related MAP kinases p38 and JNK as well as DNA damage responses in HEL cells. Although autophosphorylated JAK2-V617F was resistant to WP1130 in the ruxolitinib-persistent HEL-R cells, these cells expressed Bcl-2 and Bcl-xL at lower levels and showed an increased sensitivity to WP1130 as well as BH3 mimetics as compared with ruxolitinib-naive HEL cells. Thus, USP9X represents a promising target along with anti-apoptotic Bcl-2 family members for novel therapeutic strategies against JAK2-V617F-positive myeloproliferative neoplasms, particularly under the ruxolitinib persistence conditions.
| S-EPMC7072561 | biostudies-literature