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Статті в журналах з теми "JAK2 46"
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Pacilli, Annalisa, Paola Guglielmelli, Tiziana Fanelli, Alessandro Pancrazzi, Lisa Pieri, Rajmonda Fjerza, and Alessandro M. Vannucchi. "JAK2V617F Clonal Architecture in MPNs during JAK2 Inhibitor Treatment." Blood 126, no. 23 (December 3, 2015): 1630. http://dx.doi.org/10.1182/blood.v126.23.1630.1630.
Повний текст джерелаАнотація:
Abstract Introduction The Myeloproliferative Neoplasms (MPNs) are characterized by a recurrent point mutation of JAK2 gene (JAK2 V617F). This mutation, which usually affects only one of the JAK2 gene alleles in Essential Thrombocythemia (ET), frequently becomes homozygous in Polycythemia Vera (PV) and Myelofibrosis (MF) due to homologous mitotic recombination. A JAK2 V617F-mutated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1(GGCC), (Nat Genet 2009; 41:446) with complete linkage disequilibrium although the risk of developing MPNs is independent of the 46/1 haplotype. Furthermore, JAK2 V617F specifically arises on the 46/1 allele in most cases, thus predisposes to the development of MPN (Leukemia 2010; 24:1533; Nat Genet 2009; 41:446). These observations suggest that it is possible to define the JAK 2V617F clonal architecture starting from 46/1 SNP allele burden and the homologous recombination frequency. Aim and Methods The aim of the study was to investigate changes in the JAK2 V617F clonal structure in patients affected by PV, ET or MF and treated with ruxolitinib, a JAK1/JAK2 inhibitor recently approved for MF and PV and under investigation in ET pts intolerant of or resistant to hydroxyurea. We used a recently described methodology (Leukemia 2014;28:460) combining allele burden evaluations of both 46/1 and JAK2 and the frequency of mitotic recombination to derive the percentages of JAK2 V617F clones in MPN patients in 46/1 heterozygous patients for rs12343867 polymorphism (C/T). The JAK2 allele burden values were confirmed independently by two RTQ-PCR methods, according to Lippert (sensitivity, 0.8%) and to Larsen (sensitivity, 0.08%) method. Results We analysed 40 patients (pts) affected by MPNs (12 PV, 1 ET and 27 MF) treated with ruxolitinib over 1 to 5 years (yrs) of follow up (FU); 13 patients (32.5%) presented a reduction of at least 10% of JAK2 V617F allele burden values at latest FU: 7/12 PV (58.3%), 1/1 ET (100%), 6/27 PMF (22.2%). Among these, 9 pts with at least two years of FU were eligible for the study. A quantification of JAK2 homozygous (V617F/V617F), heterozygous (JAK2 V617F/wt) and wild type (wt/wt) clones was obtained using the methodology described above. We found a median reduction of JAK2 V617F/V617F and JAK2 V617F/wt clones of 32.31 % and 8.82 %, respectively, in PV (n.4); 12.22% and 17.86%, respectively, in MF (n.4); 35.99% and 100%, respectively, in ET (n.1). Furthermore, an almost complete molecular remission (CMR) was seen in two PV patients with 4 and 5 yrs of FU respectively and in one ET patient after 5 years of treatment. In these patients we observed reduction of homozygous clones of 99.60%, 86.91% and 100%, respectively, and the residual JAK2 allele burden was due to the persistence of JAK2 V617F/wt clones (Figure). Conversely, in one patients with an increase in JAK2 allele burden from 39% to 45% after 1,5 yrs under ruxolitinib, we observed an increase in JAK2V617F/wt but not in JAK2 V617F/V617F clones. Conclusion. Taken together, these results showed that ruxolitinib may preferentially target the homozygous clones inducing in some cases an almost complete molecular remission with prolonged treatment. Future analysis will be performed to study the clonal architecture in an increased number of patients treated with JAK inhibitors as single agent or in combination with other drugs. Figure 1. Figure 1. Disclosures Vannucchi: Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees.
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Gorre, M., I. Jilani, H. Kantarjian, F. Giles, A. Hannah, and M. Albitar. "Novel Quantitative Flow Cytometry-Based Signaling Assays Reveal a Potential Role for HSP90 Inhibitors in the Treatment of JAK2 Mutant-Positive Diseases." Blood 106, no. 11 (November 16, 2005): 3526. http://dx.doi.org/10.1182/blood.v106.11.3526.3526.
Повний текст джерелаАнотація:
Abstract The V617F mutation in the JAK2 tyrosine kinase, recently described in a majority of patients with myeloproliferative disorders (MPDs), confers growth factor independence in vitro and oncogenicity in mice. Therefore, targeted inhibition of mutant JAK2 kinase activity may be an effective strategy for treatment of MPD patients with this mutation. The ability to measure the activation status of JAK2 in patient samples will thus be of substantial value for monitoring therapeutic efficacy. We have developed quantitative flow cytometry-based assays for rapid and reproducible measurement of intracellular total and phosphorylated proteins of the canonical JAK/STAT pathway, as well as heat shock proteins (HSPs). In this study we examined the ability of these assays to detect altered levels of total and phosphorylated JAK/STAT signaling pathway components and HSP in a cell line (HEL) that is homozygous for the V617F JAK2 mutant. HEL cell cultures were incubated with 17AAG, a geldanamycin analog with clinical utility in a broad range of diseases. 17AAG exerts its inhibitory effect by binding to heat shock protein 90 (HSP90), preventing its chaperone association with client oncoproteins. AKT is among these client proteins and a component of the JAK/STAT pathway, representing a potential therapeutic target. 17AAG exposure reduced total AKT protein levels by 42%. 17AAG also inhibited mutant JAK2 activity by 66% and had a smaller effect (17%) on total JAK2 levels, suggesting that mutant JAK2 activation may rely on HSP90, either directly or through dependence on other client proteins. Exposure to 17AAG also reduced levels of P-STAT5 (50%) and, to a lesser extent, total STAT5 (27%). 17AAG-treated cells showed a 55% reduction in HSP90 levels and a 14% increase in HSP70 protein levels. JAK Inhibitor I (Calbiochem), a potent pan-JAK Inhibitor that blocks JAK1, JAK2, and JAK3 activity, caused reductions in P-JAK2 and P-STAT5 levels (29% and 26% decreases, respectively). However, the combining of JAK Inhibitor I with 17AAG did not result in an enhanced effect beyond what was observed with 17AAG treatment alone. Similar results were seen with AG490, a potent and selective JAK2 inhibitor. 17AAG caused a 40% decrease in viable cells after 18 hrs of treatment, compared with a 35% reduction for the pan-JAK inhibitor and a 20% decrease for AG490. Combining 17AAG with the pan-JAK inhibitor or AG490 caused only minor enhancement of these cytotoxic effects (46% and 41% reduction in cell viability, respectively). Our data support the potential utility of HSP90 inhibitors such as 17AAG in the development of small-molecule therapy for mutant JAK2 kinase-positive MPD. These results also show that flow cytometry-based assays for JAK/STAT signaling components and HSPs can be used to quantitatively monitor drug efficacy at the protein level in intact cells. These tests are likely to have broad clinical utility given the spectrum of diseases in which a pathogenic role for mutant JAK2 kinase is implicated.
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Xu, Lichao, Ding Zhang, Guoqiang Wang, Chao Chen, Ying Wang, Haozhe Huang, and Zhenghua Zhang. "Correlation between JAK1/2 expression and immune-related genes and JAK2 gene variants: A pan-cancer analysis." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15057-e15057. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15057.
Повний текст джерелаАнотація:
e15057 Background: Loss of function mutations for Janus kinases 1/2 (JAK1/2) have shown to be the underling mechanism of primary resistance to immune checkpoint inhibitors (ICIs). However, the correlation between JAK1/2 expression and immune-related genes have not been studied. Methods: Survival, mRNA expression and whole-exome sequencing data from 32 pan-cancer atlas studies were obtained from The Cancer Genome Atlas (TCGA). Correlations between JAK1/2 expression and immune-related genes were depicted in heatmaps. We also analyzed the association between JAK2 gene variants and JAK2 expression. Results: In total, 10071 samples with mRNA expression data were included for analysis. Expression of 46 immune-related genes were positively correlated with JAK2 expression in 25 tumors instead of JAK1 expression. Patients with higher expression of JAK2 had better prognosis than patients with lower expression of JAK2 in 13 tumors. Among 10071 patients, 363 (3.60%) patients harbored JAK2 variants, including 8 with frame shift mutations, 44 with nonsense mutations, 142 with missense mutations, 11 with splices, 8 with fusions, 90 with copy-number reduction and 116 with copy-number amplification. There was no difference in JAK2 expression between patients with JAK2 variants and those without JAK2 variants. However, JAK2 fusion (2.20%, 8/363) and amplification (31.96%, 116/363) were associated with higher JAK2 expression. Conclusions: Our pan-cancer analysis found that JAK2 expression was correlated with immune-related genes and the prognosis of cancer patients. JAK2 fusion and amplification increased the expression of JAK2. Altogether, patients with high JAK2 expression may benefit from ICIs.
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Cross, Nicholas C. P., Peter Campbell, Philip A. Beer, Susanne Schnittger, Alessandro M. Vannucchi, Katerina Zoi, Melanie Percy, et al. "The JAK2 46/1 Haplotype Predisposes to Myeloproliferative Neoplasms Characterized by Diverse Mutations." Blood 114, no. 22 (November 20, 2009): 433. http://dx.doi.org/10.1182/blood.v114.22.433.433.
Повний текст джерелаАнотація:
Abstract Abstract 433 A common constitutional JAK2 haplotype termed 46/1 (also known as GGCC) predisposes to V617F JAK2-positive myeloproliferative neoplasms (MPN) but the underlying mechanism is obscure. Two hypotheses have been postulated: (i) ‘hypermutability' of JAK2 on 46/1 compared to other haplotypes and (ii) a functional difference of JAK2 on 46/1 that positively interacts with V617F and thus provides ‘fertile ground' for development of an MPN. To investigate these possibilities we analyzed patients with essential thrombocythemia entered into the PT-1 studies. As expected, 46/1 was highly overrepresented in V617F positive cases (n=404) compared to population controls (n=1492; P=3.9×10-11) and in informative individuals V617F preferentially arose on the 46/1 chromosome (P<0.0001). This haplotype was also overrepresented in cases without V617F (n=347, P=0.009), with an excess seen for individuals with MPL exon 10 mutations as well as those who were V617F and MPL exon 10 negative. Analysis of further MPL-positive, V617F negative cases confirmed an excess of 46/1 alleles (n=176, P=0.004) however we found no association between MPL mutations and MPL haplotype. An excess of 46/1 was also seen in cases with JAK2 exon 12 mutations (n=69, P=0.002) and in informative individuals these mutations preferentially arose on the 46/1 chromosome (P=0.029). No association between 46/1 and clinical or laboratory features was seen in the PT-1 cohort either with or without V617F. An excess of 46/1 in JAK2 exon 12 mutated cases is compatible with both the hypermutability and fertile ground hypotheses, but the excess in MPL mutated cases argues against the former. However, on analysis of peripheral blood leukocytes we detected no difference in sequence, splicing or expression of JAK2 on 46/1 compared to JAK2 on other haplotypes suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle. Finally, since 46/1 is seen at comparable frequencies in different MPN subtypes it does not explain the phenotypic diversity associated with V617F JAK2. In an analysis of 138 MPL mutated cases (ET, n=99; MF, n=36; other MPN, n=3) we found that the median W515K/L mutation levels as determined by pyrosequencing in ET (21%) were significantly lower than those seen in MF (46%; P<0.0001). However we were unable to confirm previously reported differences in SNP frequencies (rs1524395 at 7p11, rs2279784 at 3q21 and rs12500918 at 4q31) between cases with ET (n=763) and PV (n=163). In summary, our data provide further evidence for the fertile ground hypothesis whereby a proposed subtle functional difference of JAK2 on 46/1 makes the development of an MPN more likely when a JAK2 mutation arises on this haplotype, or when JAK2 46/1 is present with a MPL exon 10 mutation. JAK2 and MPL mutation levels, but not 46/1 status, are related to disease phenotype. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Equity Ownership. Green:Bristol Myers Squibb: Consultancy; Shire: Consultancy; Incyte: Consultancy; Astex Therapeutics: Consultancy, Research Funding.
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Vilaine, Mathias, Damla Olcaydu, Ashot Harutyunyan, Jonathan Bergeman, Tiab Mourad, Jean-François Ramée, Jian-Min Chen, Robert Kralovics, and Sylvie Hermouet. "Homologous Recombination of Wild TYPE JAK2, A NOVEL EARLY STEP In the DEVELOPMENT of Myeloproliferative Neoplasm." Blood 118, no. 21 (November 18, 2011): 2805. http://dx.doi.org/10.1182/blood.v118.21.2805.2805.
Повний текст джерелаАнотація:
Abstract Abstract 2805 Background: Adequate expression and function of Jak2 in hematopoietic progenitors is critical for normal myelopoiesis. The JAK2 46/1 (GGCC) haplotype, a congenital particularity, predisposes to myeloproliferative neoplasm (MPN) both independently and through mutation of the JAK2 gene. The JAK2 V617F mutation and acquired homozygous status for JAK2 V617F are frequent in MPN. JAK2 V617F homozygosity is currently explained acquisition of the JAK2 V617F mutation followed by mitotic homologous recombination (HR) of JAK2 occurred between wild-type and mutant alleles, leading to uniparental disomy (UPD) of chromosome 9p (9pUPD). Here we report the cases of 2 PV patients (Na1061 and Na1253) with acquired homozygous status for the JAK2 46/1 haplotype yet their granulocytes carried <20% JAK2 V617F. Aim: To determine whether HR of JAK2 can precede the V617F mutation in MPN. Methods: Granulocyte DNA and CD3+ lymphocyte DNA were examined in parallel with qPCR assays specific for the wild type and 46/1 haplotypes using rs12343867, a JAK2 intron 14 marker, as well as 4 other single nucleotide polymorphisms (SNP) on chromosome 9p. 9pUPD clonality and length were determined using SNP array studies. Results: For both patients, lymphocytes were heterozygous for the 46/1 haplotype, confirming that granulocyte 46/1 homozygosity was acquired. Direct sequencing of the JAK2 and GNE genes and SNP array analyses revealed homologous recombination of part of the JAK2 gene (exons 6–19, patient Na1061) and of the complete 46/1 JAK2 haplotype (patient Na1253). Furthermore, for both patients, full length sequencing of JAK2 cDNA revealed no additional mutation. In both cases, HR of wild-type JAK2 was associated with growth advantage and high expression of recombined JAK2. For both patients, further SNP array analyses revealed partial 9pUPD concerning <30% cells, which correlated with %JAK2 V617F and was consistent with 9pUPD having occurred after JAK2 V617F (Figure 1). The distortion of SNP allelic differences was higher at the telomeric end than in the centromeric region of chr. 9p. This indicated 2 distinct partial 9pUPDs for Na1061 and 1 partial 9pUPD for Na1253. Conclusion: Homologous recombination involving wild type JAK2 can precede JAK2 mutation and 9pUPD in MPN. Thus multiple paths and diverse alterations of the JAK2 gene can lead to MPN in individuals carrying the JAK2 GGCC haplotype. We propose a new model with JAK2 HR as early event, followed or not by JAK2 mutation, or/and JAK2 mutation(s) facilitating subsequent recombination resulting in 9pUPD and JAK2 V617F homozygosity. Disclosures: No relevant conflicts of interest to declare.
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Jones, Amy V., Peter J. Campbell, Philip A. Beer, Susanne Schnittger, Alessandro M. Vannucchi, Katerina Zoi, Melanie J. Percy, et al. "The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms." Blood 115, no. 22 (June 3, 2010): 4517–23. http://dx.doi.org/10.1182/blood-2009-08-236448.
Повний текст джерелаАнотація:
Abstract The 46/1 JAK2 haplotype predisposes to V617F-positive myeloproliferative neoplasms, but the underlying mechanism is obscure. We analyzed essential thrombocythemia patients entered into the PT-1 studies and, as expected, found that 46/1 was overrepresented in V617F-positive cases (n = 404) versus controls (n = 1492, P = 3.9 × 10−11). The 46/1 haplotype was also overrepresented in cases without V617F (n = 347, P = .009), with an excess seen for both MPL exon 10 mutated and V617F, MPL exon 10 nonmutated cases. Analysis of further MPL-positive, V617F-negative cases confirmed an excess of 46/1 (n = 176, P = .002), but no association between MPL mutations and MPL haplotype was seen. An excess of 46/1 was also seen in JAK2 exon 12 mutated cases (n = 69, P = .002), and these mutations preferentially arose on the 46/1 chromosome (P = .029). No association between 46/1 and clinical or laboratory features was seen in the PT-1 cohort either with or without V617F. The excess of 46/1 in JAK2 exon 12 cases is compatible with both the “hypermutability” and “fertile ground” hypotheses, but the excess in MPL-mutated cases argues against the former. No difference in sequence, splicing, or expression of JAK2 was found on 46/1 compared with other haplotypes, suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle.
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Al-Ammari, Maged, Abdul Ali Peer Zada, Ibraheem H. Motabi, Belal M. Albtoosh, Syed Y. Altaf, Imran K. Tailor, Mohammed S. Alnoamani, et al. "JAK2 GGCC (46/1) Haplotype in Unprovoked Venous Thrombotic Events." Blood 138, Supplement 1 (November 5, 2021): 4258. http://dx.doi.org/10.1182/blood-2021-149560.
Повний текст джерелаАнотація:
Abstract Background: JAK2 GGCC 46/1 haplotype can be represented by four main SNPs (rs3780367, rs10974944, rs12343867, and rs1159782) which replace one cytosine and three thymidines by two guanosines and two cytosines, generating a "GGCC" combination. These four SNPs located on JAK2 introns 10, 12, 14, and 15, respectively, and are always inherited together, being in complete linkage disequilibrium. The 46/1 component of the name came from Jones et al. study where the haplotype structure of the JAK2 gene was mapped using 14 SNPs genotyped by the Wellcome Trust Case Control Consortium (WTCCC) in 1500 healthy blood donors. Two haplotypes (numbers 46 and 1) were found to be identical except for one SNP, and they have a combined frequency of 0.24 in healthy individuals. Numerous observational studies associate this haplotype with myeloproliferative neoplasms (MPNs), as well as splanchnic vein thrombosis (SVT) and non-splanchnic vein thrombosis (non-SVT). In contrast to 24% frequency noted in healthy population, the frequency goes up to 40-80% in JAK2 V617F mutated MPN, and in 64% of those with JAK2 exon 12 mutations (Anelli et al. IJMS, 2018). We herein report our study of JAK2 GGCC (46/1) Haplotype in unprovoked Venous Thrombotic Events (VTE) in patients with negative thrombophilia workup, including negative JAK2 V617F mutation. Methods: We retrospectively identified patients positive for one of the two SNPs (rs12343867 and rs10974900) and unprovoked venous thrombotic among adult patients with negative thrombophilia workup (including JAK2 mutation) treated at tertiary care center from January 2018 to January 2021. Results: We have identified 8 patients, Table (1), that were positive for JAK2 46/1 haplotype SNPs, of whom 62.5% were homozygous 2/2, 25% heterozygous 1/2, while only 12.5% harbor homozygous 1/1 (a normal variant of JAK2 haplotype). The median age 48.5 years (23-65), and the majority (87.5%) were females. Thrombosis site was noted to be SVT in half of the patients, while non-SVT was noted in the other half (12.5% had cerebral vein thrombosis, 12.5% had deep venous thrombosis, 12.5% had a pulmonary embolism, and 12.5% had jugular vein thrombosis). Half of the patients had more than one site venous thrombosis and the other half had only one site. Around 37.50% of the patients had recurrent venous thrombosis on top of therapeutic anticoagulation. Two patients (25%) had high hemoglobin (17.4/16.7) g/dl, but did not fulfill the criteria for polycythemia vera diagnosis (of whom one is a male smoker and one was a female). None of the patients had leukocytosis or thrombocytosis. By imaging, one patient had mild splenomegaly which could be related to SVT. Conclusion: We report on a potential correlation between unprovoked thrombotic events, mainly venous thrombotic events, with JAK2 46/1 haplotype in patients with a negative thrombophilia workup, a finding that merit further investigation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Olkhovskiy, I. А., M. A. Stolyar, Yu Yu Komarovskiy, A. S. Gorbenko, V. I. Korchagin, E. A. Dunaeva, K. O. Mironov, et al. "Study of the Janus kinase 2 (JAK2) gene haplotype 46/1 association with driver mutations of chronic Ph-negative myeloproliferative neoplasms." Russian journal of hematology and transfusiology 67, no. 3 (October 22, 2022): 377–87. http://dx.doi.org/10.35754/0234-5730-2022-67-3-377-387.
Повний текст джерелаАнотація:
Introduction. Haplotype JAK2 46/1 is associated with more frequent development of Ph-negative myeloproliferative neoplasms (MPN) and with an increased detection rate of the JAK2 V617F mutation. At the same time, the molecular mechanisms of such associations remain unclear. Previously, there were no studies of regional, age and gender aspects of the predictive value of carriage of the 46/1 JAK2 haplotype, which could assess this relationship in some observations.Aim — to analyze the degree of association between 46/1 haplotype and the V617F mutation of the JAK2 gene depending on the sex, age, and place of residence of patients examined for suspected MPN.Methods. The study included 949 DNA samples from patients with suspected MPN. Samples of 150 volunteers and blood donors were included in the control group. Haplotype 46/1 (rs10974944), V617F mutation in the JAK2 gene, mutations in the CALR gene (type 1: c.1092_1143del; L367fs*46, COSV57116546; type 2: c.1154_1155insTTGTC; K385fs*47, COSV57116551) and in the MPL gene (W515K, W515L) were determined for all samples using real-time polymerase chain reaction (PCR-RT).Results. The 46/1 JAK2 haplotype were shown to be associated with a clinically significant level (> 2 %) of the allelic burden of the JAK2 V617F mutation. The odds ratio of the risk of developing a V617F positive MPN when carrying this haplotype variant did not depend on the main place of residence of the patients and was found to be most pronounced in men under 50 years of age. The odds ratio of the risk did not depend on the age of the examined women.Conclusion. The association of 46/1 haplotype with the presence of other drivers of MPN mutations in the CALR or MPL genes was also statistically significant, which confirms the hypothesis of “favorable soil” rather than “hypermutability” of the JAK2 gene.
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Smalberg, Jasper, Edith Koehler, Sarwa Darwish Murad, Aurelie Plessier, Juan-Carlos Garcia-Pagan, Susana Seijó, Philippe Langlet, et al. "JAK2 Germline Genetic Variation In Budd-Chiari Syndrome and Portal Vein Thrombosis." Blood 116, no. 21 (November 19, 2010): 4212. http://dx.doi.org/10.1182/blood.v116.21.4212.4212.
Повний текст джерелаАнотація:
Abstract Abstract 4212 Primary Budd-Chiari syndrome (BCS) and non-malignant, non-cirrhotic portal vein thrombosis (PVT) are rare disorders with a considerable overlap in etiology. Myeloproliferative neoplasms (MPN) are the most frequent underlying prothrombotic factor in both entities. The JAK2 V617F mutation (VF) has been identified in over half of the individuals with MPN. Recently, a JAK2 haplotype, designated ‘46/1’, has been described. Previous studies suggest that the JAK2 46/1 haplotype represents a disease susceptibility to MPN, independent of VF status. The aim of this study was to determine the role of the JAK2 46/1 haplotype in the etiology of BCS and PVT. Patients were recruited from the EN-Vie cohort, consisting of 163 BCS and 138 PVT patients, consecutively enrolled in nine European countries between October 2003 and October 2005. DNA was available from 116 BCS patients (50 males and 66 females; median age 38.1), 97 PVT patients (47 males and 50 females; median age 49.8) and 104 healthy controls (43 males and 61 females; median age 36.8). The JAK2 46/1 haplotype was tagged by the rs12343867 single nucleotide polymorphism. Frequency of the JAK2 haplotype 46/1 was higher in BCS (36%, p=0.06) compared to controls (27%), while similar in PVT patients (28%, p=0.89). When stratified for VF status, haplotype 46/1 frequency was higher in VF positive BCS (44%, p=0.01) and VF positive PVT patients (40%, p=0.06) compared to controls. Haplotype 46/1 frequency was similar in VF negative BCS (33%, p=0.29) and PVT patients (24%, p=0.47) compared to controls. VF negative BCS patients with a proven MPN also showed increased frequency of the 46/1 haplotype (56%, p=0.07). Logistic regression, adjusted for age and sex, showed an association between the 46/1 haplotype and risk of VF positive BCS (OR: 2.10; 1.16–3.80), VF positive PVT (OR 2.07; 0.95–4.52) and VF negative BCS patients with a proven MPN (OR 3.04; 1.02–9.06). We conclude that the JAK2 46/1 haplotype may be associated with BCS and that this was limited to patients with a proven MPN, independent of VF status. In PVT, the 46/1 haplotype was only associated with patients who were VF positive. This study was carried out on behalf of the European Network for Vascular Disorders of the Liver (EN-Vie). Disclosures: No relevant conflicts of interest to declare.
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Cross, Nicholas C. P., Amy V. Jones, Richard T. Silver, David Oscier, Georgia Metzgeroth, Y. Lynn Wang, Andrew Collins, Andreas Reiter, Francis Grand, and Andrew Chase. "Development of V617F JAK2 Associated Myeloproliferative Neoplasms Is a Non-Random Event That Is Strongly Dependent on JAK2 Haplotype." Blood 112, no. 11 (November 16, 2008): 173. http://dx.doi.org/10.1182/blood.v112.11.173.173.
Повний текст джерелаАнотація:
Abstract Epidemiological data and family studies have indicated that inherited factors may predispose to the development of myeloproliferative neoplasms (MPN). It has also been suggested that single nucleotide polymorphisms (SNPs) within JAK2 are associated with specific MPN subtypes. To explore the role of inherited factors in more detail, we initially performed quantitative analysis of a series of JAK2 SNPs in homozygous PV cases (%V617F >50%; n=73). Most mutant haplotypes could be read directly from the distorted allele ratios brought about by expansion of the homozygous clone. In many cases with 50–90% V617F, the residual wild type haplotype could also be read. Strikingly, of the 144 V617F alleles that could be determined, 111 (77%) had an identical core haplotype (subsequently designated 46/1) whereas only 9/76 (12%) residual wild type alleles were 46/1 (P = 1.9e-21, Fisher’s exact test). To explore this observation in more detail we first determined the haplotype structure of JAK2 using 14 SNPs genotyped by the Wellcome Trust Case Control Consortium (WTCCC) in 1500 UK blood donors. Nine haplotypes were inferred using the program PHASE that accounted for 94% of alleles, with a frequency of 0.24 for haplotype 46/1. Haplotype inference and tag SNP analysis revealed that 46/1 was also more frequent in heterozygous V617F positive MPD cases (135/354 alleles) compared to 188 locally sourced healthy controls (92/376 alleles; P = 0.0001) as well as the WTCCC cohort (P = 3.3e-8). Haplotype 46/1 was more frequent in all V617F positive disease entities compared to controls: PV (n=203; P=1.2e-16), ET (n=81; P=1.2e-9) and MF (n=41; P=8.0e-5) however there was no difference in the frequency of 46/1 between controls and V617F negative MPD / idiopathic erythrocytosis (n=123). To determine if heterozygous V617F also preferentially arose on a 46/1 allele as seen for homozygous cases, we developed an allele specific PCR between V617F and a SNP that tags this haplotype. In an analysis of 67 informative heterozygous V617F cases, 50 V617F alleles were 46/1 compared to only 17 residual wild type alleles (P=9.4e-9). We conclude that the 46/1 JAK2 haplotype is a strong predisposition factor for development of V617F associated MPDs (RR=2.6; 95% CI 2.3–2.9). The reason for this predisposition is currently unknown but it is likely that 46/1 is in linkage disequilibrium with an unknown constitutional functional variant that interacts with V617F JAK2.
Дисертації з теми "JAK2 46"
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SPOLVERINI, AMBRA. "Analysis of polymorphic variants and new mutations in patients with Chronic Myeloporiliferative Neoplasms." Doctoral thesis, 2013. http://hdl.handle.net/2158/796256.
Повний текст джерелаАнотація:
Studio del possibile ruolo dell'aplotipo 46/1 del gene JAK2 nella predisposizione allo sviluppo di leucemia mieloide cronica. Studio della frequenza di casi di LMC che presentano oltre al trascritto di fusione BCR/ABL la mutazione JAK2V617F. Studio del possibile ruolo di un aplotipo della regione 12q24 nella predisposizione genetica allo sviluppo di neoplasie mieloproliferative. Studio dell'incidenza di mutazioni di LNK in pazienti con eritrocitosi idiopatica. Studio del possibile ruolo delle proteine 14-3-3 nella patogenesi delle neoplasie mieloproliferative
Частини книг з теми "JAK2 46"
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Klimkowski, Marceli. "Profesor Danuta Kądzielawa a kształtowanie się neuropsychologii jako dziedziny neuronauk..." In Studia z neuropsychologii klinicznej. Na 45-lecie pracy zawodowej Profesor Danuty Kądzielawy. Warsaw University Press, 2014. http://dx.doi.org/10.31338/uw.9788323514442.pp.46-50.
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Cegiełka, Anna. "Słownik jako tekst kultury określonego czasu – na przykładzie wybranych słowników języka angielskiego." In Leksykografia w różnych kontekstach. Tom 2. Warsaw University Press, 2020. http://dx.doi.org/10.31338/uw.9788323541677.pp.35-46.
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Kozioł, Kamila. "Traktat Naehun jako kanon nauk moralnych dla kobiet i jego znaczenie w XV-wiecznej Korei." In Koreańskie światy kobiet – między dziedzictwem konfucjanizmu a wyzwaniami współczesności. University of Warsaw Press, 2019. http://dx.doi.org/10.31338/uw.9788323539001.pp.13-46.
Повний текст джерелаТези доповідей конференцій з теми "JAK2 46"
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Murgaš, František. "Kvalita místa jako vyjádření objektivní dimenze kvality života." In XXI. mezinárodní kolokvium o regionálních vědách. Brno: Masarykova univerzita, 2018. http://dx.doi.org/10.5817/cz.muni.p210-8970-2018-46.
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