Jak2 Tyrosine Kinase: A True Jak of All Trades?

Sandberg, Eric M.; Wallace, Tiffany A.; Godeny, Michael D.; VonDerLinden, Danielle; Sayeski, Peter P.

doi:10.1385/cbb:41:2:207

Cited by 46 publications

(40 citation statements)

References 140 publications

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“…JAK2 gene is on 9th chromosome and this point mutation was identified in BCR-ABL negative MPD in 2005. [2][3][4][5][6] According to the studies, JAK2 V617F mutation is seen 97% of PV, 57% of ET and 50% of IMF. 3 In addition, JAK2 V617F mutation has been identified in atypical MPD, myelodysplastic syndrome, and erytroleukemia.…”

Section: Introductionmentioning

confidence: 99%

JAK 2V617F Mutation: Frequency and Relation to Clinical and Laboratory Features of BCR-ABL Negative Myeloproliferative Diseases

İlhan¹,

Karakuş²,

Şahin³

2012

UHOD

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In this study, we planned to investigate frequency of the JAK2 V617F mutation and it's relation with clinical and laboratory findings of BCR-ABL negative myeloproliferative diseases (MPD) which consist of polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Totally 65 patients were included in the study which composed of 28 (43.1 %) PV, 29 (44 %) ET and 8 (12.3 %) IMF patients. Forty one (63%) patients were female and 24 (37%) were male. Mean age of patients was 64.02±12.42. Frequency of the JAK2V617F mutation was found in 25 (89.3%) of PV, 18 (62.1%) of ET and 2 (25%) of IMF patients. We found no difference in gender and frequency of thrombosis, constitutional symptoms, pruritus, hemorrhage, splenomegaly, bone marrow fibrosis, cytoreductive treatment requirement, arterial/venous thrombosis between JAK2 V617F mutated and unmutated PV and ET and IMF patients. When compared homozygous and heterozygous JAK2 V617F mutated PV and ET patients according to these variables, there was no significant difference. There were no statistically significant difference in Hemoglobin (Hb), hematocrit (HCT), leukocyte, lactate dehidrogenase (LDH), EPO and ferritin levels between JAK2 V617F mutated and unmutated PV and ET patients. HCT levels and leukocyte counts were significantly higher in JAK2 V617F mutated than unmutated IMF patients (p=0.046, p=0.046). Other variables were not found different. Comprehensive prospective studies are necessary for determining the relationship of the JAK2 V617F mutation with clinical and laboratory findings . 3), ET hastalar›n›n 18'inde (% 62.1) ve IMF hastalar›n›n 2'sinde (%25) olarak bulundu. JAK2 V617F mutasyonu olan ve olmayan PV ve ET ve IMF hastalar› aras›nda cinsiyet, tromboz s›kl›¤›, konstitüsyonel semptomlar, pruritus, hemoraji, splenomegali, kemik ili¤i fibrozisi, sitoredüktif tedavi ihtiyac›, arteriyel/venöz tromboz geliflimleri aç›s›ndan bir fark bulamad›k. Heterozigot ve homozigot JAK2 V617F mutasyonu olan PV ve ET hastalar›, bu parametreler aç›s›ndan karfl›laflt›r›ld›¤›nda, anlaml› bir fark yoktu (p>0.05).

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Section: Introductionmentioning

confidence: 99%

JAK 2V617F Mutation: Frequency and Relation to Clinical and Laboratory Features of BCR-ABL Negative Myeloproliferative Diseases

İlhan¹,

Karakuş²,

Şahin³

2012

UHOD

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“…This pathway is activated by a diversity of receptors, including receptor tyrosine kinases [38,45,51] and Gprotein-coupled receptors [11,33]. Upon activation of JAK, STAT proteins dimerize and translocate to the nucleus, where they mediate gene transcription (reviewed by Sandberg et al [36]). In myocardial tissue it can be difficult to distinguish which receptor system is responsible for activation of JAK/STAT signalling [12].…”

Section: Introductionmentioning

confidence: 99%

Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion

et al. 2008

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Objective-To evaluate the significance of the JAK-STAT pathway in insulin-induced cardioprotection from reperfusion injury. Correspondence to: Britt N. Fuglesteg, brittf@fagmed.uit.no Methods-In isolated perfused rat hearts subjected to insulin therapy (0.3 mU/ml) ± AG490 (5 μM, JAK-STAT inhibitor), the phosphorylation state of STAT3 and Akt was determined after 15 min of reperfusion. Infarct size was measured after 120 min of reperfusion. Isolated cardiac myocytes from wild type (WT) and cardiac specific STAT3 deficient mice were treated with insulin at reoxygenation following simulated ischemia (SI, 26 h). Cell viability was measured after 120 min of reoxygenation following SI, whereas phosphorylation state of Akt was measured after 15 min of reoxygenation following SI.Results-Insulin given at reperfusion led to phosphorylation of STAT3 and Akt both of which were inhibited by AG490. AG490 also blocked the insulin-dependent decrease in infarct size, supporting a role for JAK-STAT in cardioprotection. In addition, insulin protection from SI was blocked in myocytes from the STAT3 deficient mice, or in WT mice treated with AG490. Furthermore, insulin failed to phosphorylate Akt in the STAT3 deficient cardiomyocytes.Conclusion-Insulin-induced cardioprotection at reperfusion occurs through activation of STAT3. Inhibiting STAT3 by AG490, or STAT3 depletion in cardiac myocytes affects activation of Akt, suggesting close interaction between STAT3 and Akt in the cardioprotective signalling pathway activated by insulin treatment at reperfusion.

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“…JAK family members play a crucial role in the immune system; for example, inherited JAK3 deficiency causes severe combined imunodeficiency, 49,50 and JAK2 also plays an important role in cardiovascular signaling systems. 51 Development of inhibitors that inhibit V617F without undesirable side effects may therefore be challenging.Diagnosis of MPDs is often complex, expensive and in the case of ET, based solely on exclusion criteria. Since the detection of acquired V617F is simple to perform and unambiguously establishes the presence of a clonal disorder, we believe that JAK2 mutation testing will rapidly become a frontline test for individuals with a suspected diagnosis of an MPD.…”

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confidence: 99%

Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders

Jones

Kreil

Zoi

et al. 2005

Blood

777

605

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The analysis of rare chromosomal translocations in myeloproliferative disorders has highlighted the importance of aberrant tyrosine kinase signaling in the pathogenesis of these diseases. Here we have investigated samples from 679 patients and controls for the nonreceptor tyrosine kinase JAK2 V617F mutation. Of the 480 myeloproliferative disorder (MPD) samples, the proportion of positive cases per disease subtype was 30 (20%) of 152 for atypical or unclassified MPD, 2 of 134 (2%) for idiopathic hypereosinophilic syndrome, 58 of 72 (81%) for polycythemia vera, 24 of 59 (41%) essential thrombocythemia (ET), and 15 of 35 (43%) for idiopathic myelofibrosis. V617F was not identified in patients with systemic mastocytosis (n ‫؍‬ 28), chronic or acute myeloid leukemia (n ‫؍‬ 35), secondary erythrocytosis (n ‫؍‬ 4), or healthy controls (n ‫؍‬ 160). Homozygosity for V617F was seen in 43% of mutant samples and was closely correlated with chromosome 9p uniparental disomy. Homozygosity was significantly less common in ET compared with other MPD subtypes. In 53 cases analyzed, the median level of PRV1 expression was significantly higher in V617F-positive cases compared with cases without the mutation. We conclude that V617F is widespread in MPDs. IntroductionChronic myeloproliferative diseases (CMPDs) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid cell lineages in the bone marrow and increased numbers of mature and immature cells in the peripheral blood. CMPDs include polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) and chronic myeloid leukemia (CML), plus rarer subtypes such as chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), and chronic eosinophilic leukemia (CEL). These diseases overlap with myelodysplastic/myeloproliferative diseases (MDS/MPDs) such as atypical CML (aCML) and chronic myelomonocytic leukemia (CMML), in which proliferation is accompanied by dysplastic features or ineffective hematopoiesis in other lineages. 1 We refer here broadly to all these groups as myeloproliferative disorders (MPDs).Although there are strict diagnostic criteria for MPD subtypes, precise categorization remains a subject of debate 2 and furthermore, it can be difficult to differentiate some cases from reactive disorders. Only CML is characterized by a pathognomonic molecular marker, the BCR-ABL fusion, and the primary abnormalities driving excess proliferation in most other cases have been obscure. However, several lines of evidence have implicated aberrant tyrosine kinase signaling as the root cause of MPDs. Breakpoint cluster region-abelson (BCR-ABL) itself is a constitutively active tyrosine kinase that is believed to be the primary, and probably the only, driving force behind chronic-phase CML. 3 Other gene fusions have been identified in rare cases of aCML, CMML, and HES/CEL that involve the tyrosine kinases PDGFRA, PDGFRB, FGFR1, and JAK2. 4,5 In addition, the KIT receptor is activated by point mutation in the majority...

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Jak2 Tyrosine Kinase: A True Jak of All Trades?

Cited by 46 publications

References 140 publications

JAK 2V617F Mutation: Frequency and Relation to Clinical and Laboratory Features of BCR-ABL Negative Myeloproliferative Diseases

JAK 2V617F Mutation: Frequency and Relation to Clinical and Laboratory Features of BCR-ABL Negative Myeloproliferative Diseases

Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion

Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders

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