Artículos de revistas: "JAK2 46"

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Pacilli, Annalisa, Paola Guglielmelli, Tiziana Fanelli, Alessandro Pancrazzi, Lisa Pieri, Rajmonda Fjerza y Alessandro M. Vannucchi. "JAK2V617F Clonal Architecture in MPNs during JAK2 Inhibitor Treatment". Blood 126, n.º 23 (3 de diciembre de 2015): 1630. http://dx.doi.org/10.1182/blood.v126.23.1630.1630.

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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 y 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, n.º 11 (16 de noviembre de 2005): 3526. http://dx.doi.org/10.1182/blood.v106.11.3526.3526.

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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 y Zhenghua Zhang. "Correlation between JAK1/2 expression and immune-related genes and JAK2 gene variants: A pan-cancer analysis." Journal of Clinical Oncology 38, n.º 15_suppl (20 de mayo de 2020): e15057-e15057. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15057.

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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, n.º 22 (20 de noviembre de 2009): 433. http://dx.doi.org/10.1182/blood.v114.22.433.433.

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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 y Sylvie Hermouet. "Homologous Recombination of Wild TYPE JAK2, A NOVEL EARLY STEP In the DEVELOPMENT of Myeloproliferative Neoplasm". Blood 118, n.º 21 (18 de noviembre de 2011): 2805. http://dx.doi.org/10.1182/blood.v118.21.2805.2805.

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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, n.º 22 (3 de junio de 2010): 4517–23. http://dx.doi.org/10.1182/blood-2009-08-236448.

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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 (5 de noviembre de 2021): 4258. http://dx.doi.org/10.1182/blood-2021-149560.

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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, n.º 3 (22 de octubre de 2022): 377–87. http://dx.doi.org/10.35754/0234-5730-2022-67-3-377-387.

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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, n.º 21 (19 de noviembre de 2010): 4212. http://dx.doi.org/10.1182/blood.v116.21.4212.4212.

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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 y Andrew Chase. "Development of V617F JAK2 Associated Myeloproliferative Neoplasms Is a Non-Random Event That Is Strongly Dependent on JAK2 Haplotype". Blood 112, n.º 11 (16 de noviembre de 2008): 173. http://dx.doi.org/10.1182/blood.v112.11.173.173.

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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.

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Tefferi, Ayalew, Terra L. Lasho, Christy Finke, Mythri Mudireddy, Natasha Szuber, Rangit Reddy Vallapureddy, Domenico Penna et al. "The Germline JAK2 GGCC (46/1) Haplotype and Survival Among 414 Molecularly-Annotated Patients with Primary Myelofibrosis". Blood 132, Supplement 1 (29 de noviembre de 2018): 1761. http://dx.doi.org/10.1182/blood-2018-99-110046.

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Abstract Background: We have long introduced the concept of host genetic variations in the phenotypic diversity of myeloproliferative neoplasms (MPN) (Blood 2008;111:2785). Previous studies have established an association between JAK2 mutations in myeloproliferative neoplasms (MPN) and the germline GGCC (46/1) haplotype, which constitutes a string of single nucleotide polymorphisms (SNPs) near the JAK2 gene that are inherited together on chromosome 9p (reviewed recently;Int J Mol Sci. 2018; 19: 1152). In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype (Leukemia 2010; 24:105), although our findings were not confirmed in another study (Leukemia 2010; 24:1533). Others have reported an association with splanchnic vein thrombosis, that was not accounted for by JAK2 mutations (Ann Hematol 2014;93:1845). In the current study, we have increased the number of informative cases to 414 (from 130 reported in 2010), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. Methods : Study patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses PMF and its leukemic transformation were confirmed by both clinical and bone marrow examinations, in line with the 2016 World Health Organization criteria (Blood. 2016;127:2391). Screening for the JAK2 46/1 haplotype included rs12343867 SNP genotyping, as previously detailed (Leukemia 2010; 24:105), and using a commercially available TaqMan SNP genotyping assay (Applied Biosystems Inc., Foster City, CA, USA). Statistical analyses considered clinical and laboratory data collected at the time of initial PMF diagnosis or Mayo Clinic referral point. Conventional statistics was used for confirming phenotypic associations and calculation of overall (OS) and leukemia-free (LFS) survival. The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations. Results: 414 patients with PMF (median age 63 years; 63% males) were included in the current study; among 324 evaluable cases, MIPSS70+ version 2.0 risk distribution was 18% very high risk, 41% high risk, 19% intermediate risk, 18% low risk and 4% very low risk. Driver mutation distribution was 63% JAK2, 17% type 1-like CALR, 3% type 2-like CALR, 7% MPL and 10% triple-negative. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1-like CALR, 3%/2%/5% type 2-like CALR, 4%/8%/7% MPL and 6%/10%/14% triple-negative (p=0.02). The three 46/1 haplotype groups were phenotypically mostly similar, with the exception of platelet count (p=0.02) and leukocyte count (p=0.003), which were both higher with homozygous 46/1 haplotype. In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1-1.9; figure 1a); this survival effect was most pronounced in JAK2 mutated cases (figure 1b; p<0.001), as opposed to CALR/MPL mutated cases (figure 1c; p=0.48) or triple-negative cases (figure 1d; p=0.27). Multivariable analysis that included age and other genetic risk factors, including karyotype, driver mutational status and presence of high molecular risk mutations, such as ASXL1 and SRSF2, confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (p=0.02; HR 1.4, 95% CI 1.1-1.8). Nullizygosity for 46/1 also remained significant in the context of the recently unveiled genetics-based prognostic model, GIPSS (genetically-inspired prognostic scoring system) (p=0.04) (Leukemia.2018 doi: 10.1038/s41375-018-0107-z), but not in the context of MIPSS70+ version 2.0 (karyotype and mutation-enhanced international prognostic scoring system for transplant-age patients) (p=0.4). (JClinOncol.2018 doi: 10.1200/JCO.2018.78.9867). Leukemia-free survival was not affected by the 46/1 haplotype (p=0.6). Conclusions: The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in PMF, primarily in JAK2-mutated cases; the observed survival effect was independent of currently acknowledged genetic risk factors, including karyotype and high molecular risk mutations. Disclosures No relevant conflicts of interest to declare.

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Kouroupi, Eirini, Jean-Jacques Kiladjian, Christine Chomienne, Christine Dosquet, Sylvia Bellucci, Dominique Valla y Bruno Cassinat. "The JAK2 46/1 haplotype in splanchnic vein thrombosis". Blood 117, n.º 21 (26 de mayo de 2011): 5777–78. http://dx.doi.org/10.1182/blood-2011-03-343657.

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13

Macedo, L. C., B. C. Santos, S. Pagliarini-e-Silva, K. B. B. Pagnano, C. Rodrigues, F. C. Quintero, M. E. Ferreira et al. "JAK2 46/1 haplotype is associated with JAK2 V617F - positive myeloproliferative neoplasms in Brazilian patients". International Journal of Laboratory Hematology 37, n.º 5 (11 de mayo de 2015): 654–60. http://dx.doi.org/10.1111/ijlh.12380.

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14

Tanaka, Mayumi, Toshiaki Yujiri, Shunsuke Ito, Naoko Okayama, Toru Takahashi, Kenji Shinohara, Yoichi Azuno, Ryouhei Nawata, Yuji Hinoda y Yukio Tanizawa. "JAK2 46/1 haplotype is associated with JAK2 V617F-positive myeloproliferative neoplasms in Japanese patients". International Journal of Hematology 97, n.º 3 (22 de febrero de 2013): 409–13. http://dx.doi.org/10.1007/s12185-013-1295-y.

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15

Panovska, Irina, Nadica Matevska, Martin Ivanovski, Sanja Trajkova, Dusko Dukovski, Lidija Cevreska y Aleksandar Dimovski. "Frequency and Clinical Correlates of JAK2 46/1 Haplotype in Comparison with JAK2V617F Variant in Myeloproliferative Neoplasms: Single Center Experience". Blood 118, n.º 21 (18 de noviembre de 2011): 5173. http://dx.doi.org/10.1182/blood.v118.21.5173.5173.

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Abstract Abstract 5173 It is predicted that the inherited genetic background in the individual patients with myeloproliferative neoplasm (MPN) influences the disease susceptibility and the phenotype expression of the MPN. Recently, several groups suggested that JAK2V617F positive MPN are acquired preferentially on a specific constitutional germline JAK2 46/1 haplotype which is tagged by the “C” allele of single nucleotide polymorphism (SNP) rs12343867 (C/T), and designate the genetic basis for predisposition to MPN. They try to explain the pathomechanism for the acquisition of V617F mutation trough the “hypermutability hypothesis” suggesting as a main mechanism the genomic instability at the JAK2 locus. But, subsequent data, showed equal distribution of this SNP among JAK2V617F negative MPN, indicating that it is a potential common inherited susceptibility factor for MPN. Moreover, only few studies investigated the potential role of the JAK2 46/1 haplotype at the MPN phenotype in context of the clinical presentation and the complication of the diseases. In order to extend further those observations we conduct a retrospective study. First, we assess the frequency of JAK2 46/1 haplotype in a group of patients with MPN in comparison with population controls. As second we evaluate the association of 46/1 with the JAK2V617F mutational status and the clinical characteristics in the series of patients with different entities of MPN that were diagnosed and treated at the University Clinic of hematology-Skopje, Republic of Macedonia. The study group consisted of 212 adult (>15 years) patients with MPNs that were diagnosed and followed at the University Clinic of Hematology- Skopje. According to the 2008 World Health Organization criteria 79 patients were diagnosed as Polycythemia vera (PRV), 95 as Essential thrombocythemia (ET), 10 as Myelofibrosis primaria (MF) and 28 were classified as atypical MPN (aMPN). The 46/1 tag SNP rs12343867 (C/T) was genotyped using the TaqMan SNP genotyping assay (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions. The JAK2 V617F mutation was analyzed by fluorescent allele-specific PCR followed by CE on ABI 310 Genetic analyzer. The incidence of 46/1-linked C allele was significantly higher in all MPN entities [PRV (0.538), ET (0.437), MF (0,464), and in aMPN (0.55)] in comparison with healthy controls (0.290); (P<0,01 for all comparisons). The frequency of the JAK2V617F mutation ranged from 89%in PRV, 67% in ET, 60% in MF to 46,4% in the aMPN. The frequency of the JAK246/1 C allele was significantly higher in the JAK2V617F positive patients with PRV, MF and aMPN; (p<0,01 for all comparisons) except in ET patients, in which genotype distributions were similar among JAK2V617F positive and JAK2V617F negative patients (genotype: CC 7/14%, CT 22/29%, TT 67/57%; C-allele frequency 41/43%; p=0,76) Correlations of the clinical features at diagnosis and long-term prognosis between the two JAK2 46/1 different MPNs groups revealed comparability regarding all tested parameters such as blood counts, NAP score, rate of thrombotic and hemorrhagic complications, disease transformation and survival Our results confirmed latest observations that JAK2 46/1 haplotype is a susceptibility factor for developing ET independent of JAK2V617F mutational status. They also showed that the JAK2 46/1 haplotype does not affect the clinical course and prognosis of the different entities of MPN neoplasm. Our findings indicate that JAK2 46/1 haplotype predispose for development of MPN trough “the fertile ground hypothesis” which suggest that cells that are carrying the haplotype gain selective advantages in situations when oncogenic mutations occur. Disclosures: No relevant conflicts of interest to declare.

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Stolyar, M. A., O. A. Klimova, A. S. Gorbenko, E. V. Brenner, S. E. Titov, M. K. Ivanov y I. A. Olkhovskiy. "JAK2 haplotype 46/1 and JAK2 V617F allele burden in MPN: New evidence against the “hypermutability” hypothesis?" International Journal of Laboratory Hematology 40, n.º 1 (14 de noviembre de 2017): e8-e10. http://dx.doi.org/10.1111/ijlh.12765.

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17

Weiler, SR, S. Mou, CS DeBerry, JR Keller, FW Ruscetti, DK Ferris, DL Longo y D. Linnekin. "JAK2 is associated with the c-kit proto-oncogene product and is phosphorylated in response to stem cell factor". Blood 87, n.º 9 (1 de mayo de 1996): 3688–93. http://dx.doi.org/10.1182/blood.v87.9.3688.bloodjournal8793688.

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Stem cell factor (SCF) is a hematopoietic growth factor that interacts with the receptor tyrosine kinase, c-kit. We have found that SCF- stimulates rapid and transient tyrosine phosphorylation of JAK2 in human and murine cell lines, as well as in normal human progenitor cells. JAK2 and c-kit were associated in unstimulated cells with further recruitment of JAK2 to the c-kit receptor complex after SCF stimulation. Treatment of cells with JAK2 antisense oligonucleotides resulted in a 46% decrease in SCF-induced proliferation. These data demonstrate that SCF induces tyrosine phosphorylation of JAK2 and suggest that JAK2 is a component of the SCF signal transduction pathway.

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18

Cleyrat, Cédric, Jaroslav Jelinek, François Girodon, Marjorie Boissinot, Thierry Ponge, Jean-Luc Harousseau, Jean-Pierre Issa, Sylvie Hermouet y Sylvie Hermouet. "Polycythemia Vera with Multiple Clones Carrying Different Mutations (L611V, V617F, L611V/V617F) in Exon 14 of JAK2." Blood 114, n.º 22 (20 de noviembre de 2009): 3908. http://dx.doi.org/10.1182/blood.v114.22.3908.3908.

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Abstract Abstract 3908 Poster Board III-844 Background In more than 95% of cases, Polycythemia vera (PV) is characterized by the presence of the V617F mutation of JAK2 (JAK2-V617F). We report on three cases of V617F-positive PV with an additional mutation of JAK2 changing leucine 611 for a valine (L611V). Design and Methods We used allele-specific quantitative PCRs and pyro-sequencing to detect the L611V and V617F JAK2 mutants in genomic DNA and in cloned PCR products. The consequences of the different mutations on the function of JAK2 were investigated using transient expression in BaF-3/EpoR cells. Results We found equal proportions of L611V and V617F alleles in granulocyte DNA (patients Na249, 19%; Na382, 26%; Di362, 27%) and established the presence of alleles with L611V and V617F in cis (L611V/V617F). The double JAK2-L611V/V617F mutant represented 15% to 26% of JAK2 alleles in granulocyte DNA. JAK2-L611V/V617F was detected in 12% to 30% of erythroid colonies, always in a heterozygous fashion. Low levels of single mutant alleles were also found, in 0.5% of cloned PCR products (JAK2-L611V, patient Na249) and in 1.5% of genomic DNA and cloned PCR products (JAK2-V617F, patient Na249), indicating that mutations in JAK2 occurred more than once. Functionally, JAK2-L611V was found comparable to wild-type JAK2, whereas JAK2-L611V/V617F displayed greater constitutive tyrosine phosphorylation of JAK2 and AKT than wild-type JAK2 and JAK2-V617F. The double JAK2-L611V/V617F mutant was associated with a high hematocrit and normal counts of leukocytes and platelets. Patients Na382 and Di362, but not patient Na249, carried the 46/1 haplotype of chromosome 9p associated with a reported pre-disposition to mutations of JAK2 on the same allele. Conclusion PV patients can harbor multiple clones carrying different mutations of JAK2, which may or may not increase JAK2 activity. Functionally silent mutations, not leading to clonal expansion, may remain undetected. The double JAK2-L611V/V617F mutated clone was predominant whereas single L611V and V617F JAK2 mutants represented <2% of JAK2 alleles. Thus presence of the activating JAK2-V617F mutation does not ensure clonal expansion, implying that other factors promote or repress expansion of JAK2-mutated progenitors. Lastly, mutations of JAK2 can occur more than once in patients negative for the pre-disposing 46/1 haplotype. Disclosures: No relevant conflicts of interest to declare.

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Angona, Anna, Beatriz Bellosillo, Alberto Alvarez-Larrán, Luz Maria Martinez-Aviles, Laura Camacho, Silvia Pairet, Concepción Fernández y Carles Besses. "Genetic Predisposition to Molecular Response in Patients with Myeloproliferative Neoplasms Treated with Hydroxycarbamide". Blood 120, n.º 21 (16 de noviembre de 2012): 1738. http://dx.doi.org/10.1182/blood.v120.21.1738.1738.

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Abstract Abstract 1738 Introduction: Hydroxycarbamide (HC) is an antimetabolite used as first-line therapy in high risk essential thrombocythemia (ET) and polycythemia vera (PV). In treatment-naive patients, HC achieves complete hematological and partial molecular response in 80% and 50% of patients, respectively. Genetic factors involved in the pharmacokinetics of HC, as well as in the acquisition of the JAK2V617F mutation, could play a role in the variability among these patients in achieving a molecular response. Objective: To assess the influence of 46/1 JAK2 haplotype and urea transporters polymorphisms on the molecular response in JAK2V617F-positive PV and ET patients treated with HC. Methods: JAK2V617F allele burden was measured by quantitative PCR at diagnosis and every 6 months during follow-up in 53 PV patients and in 41 ET patients receiving HC therapy. Molecular response to HC treatment was defined according to European LeukemiaNet (ELN) criteria. SNPs rs12340895 and rs12343867 were used to determine 46/1 haplotype status and SNPs rs2298720 (SLC14A1), rs9960464 (SLC14A2), were used to genotype urea transporters. The rate of molecular response was compared according to 46/1 JAK2 haplotype status (negative, heterozygous, homozygous), and genotype of 2 urea transporters: SLC14A1 (GG, GA, AA) and SLC14A2 (GG, GA, AA). The study was approved by the local Ethics Committee and informed consent was obtained according to the Declaration of Helsinki. Results: Overall, molecular response (CR or PR) was achieved in 48 patients (51%), corresponding to 46% and 57% in PV and ET patients, respectively (p=0.3). In ET patients, there were no significant differences in the proportion of patients achieving a molecular response according to 46/1 JAK2 haplotype or to the different transporter genotypes. PV patients with the GG genotype in transporter SLC14A2 obtained more frequently a molecular response than those with AA or GA genotype (71% versus 36%, p=0.03). No significant differences in molecular response were observed in PV patients according to transporter SLC14A1 and 46/1 JAK2 haplotype. Conclusion: 46/1 JAK2 haplotype status did not influence molecular response in PV or ET patients treated with HC. Polymorphisms in urea transporters showed a minimal effect on the rate of molecular response in these patients. Disclosures: No relevant conflicts of interest to declare.

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Trifa, Adrian P., Andrei Cucuianu, Ljubomir Petrov, Laura Urian, Mariela S. Militaru, Delia Dima, Ioan V. Pop y Radu A. Popp. "The G allele of the JAK2 rs10974944 SNP, part of JAK2 46/1 haplotype, is strongly associated with JAK2 V617F-positive myeloproliferative neoplasms". Annals of Hematology 89, n.º 10 (27 de abril de 2010): 979–83. http://dx.doi.org/10.1007/s00277-010-0960-y.

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Hasan, Salma, Jean Pierre Le Couedic, Fabrizia Favale, Barbara Monte-Mor, Catherine Lacout, Nicole Casadevall, Eric Solary, Jean-Luc Villeval, Isabelle Plo y William Vainchenker. "46/1 Haplotype Permits to Follow JAK2 Homologous Recombination: Modeling JAK2V617F clonal Architecture in PV Patients". Blood 120, n.º 21 (16 de noviembre de 2012): 1757. http://dx.doi.org/10.1182/blood.v120.21.1757.1757.

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Abstract Abstract 1757 Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) disorders characterized by excess proliferation of one or several myeloid lineages. More than 95% polycythemia vera (PV) and 50–60% essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients harbor a somatic 1849 G>T mutation in JAK2 gene. Moreover about 30% of PV patients are homozygous for this mutation due to a loss of heterozygosity after a mitotic homologous recombination (HR). Among 92 haplotypes of chromosome 9p, 46/1 haplotype is strongly associated with the cis-aquisition of JAK2V617F mutation. The purpose of this study was to estimate the clonal frequency of WT, JAK2V617F/+ and JAK2V617F/V617F in progenitors compartments. Here, we have modeled the JAK2V617F clonal architecture in 9 PV patients heterozygous for the 46/1 haplotype by using the level of JAK2 and the 46/1 haplotype as a marker to follow HR. First we measured the global JAK2V617F and 46/1 allele burden in CD34+ cells either by allele-specific PCR or by Ion Torrent sequencing in order to calculate the expected WT, JAK2V617F/+ and JAK2V617F/V617F clones. Next, we compared the results with the experimental clonal frequency of WT, JAK2V617F/+ and JAK2V617F/V617F cells in individual colonies derived from the CD34+CD38+ compartment. In majority of patients, the observed values corresponded to the expected values suggesting that JAK2 46/1 haplotype can be used to estimate JAK2V617F clonal structure in PV patients. In three JAK2 46/1 heterozygous hemochromatosis patients used as controls, no JAK2 46/1 homozygous clone was observed showing that 46/1 haplotype itself was not responsible for HR. Furthermore, we have studied the proliferative advantage of the mutated clones in patients. No proliferative advantage of JAK2V617F clone has been observed in between CD34+CD38− and CD34+CD38+ progenitors stages whereas strong amplification of JAK2V617F clone was found in terminally differentiated polynuclear neutrophils (PNN). Moreover, during evolution of MPN in one patient, we observed an amplification of the JAK2V617F/V617F clone in both the CD34+CD38− and CD34+CD38+cell compartments suggesting acquisition of a proliferative advantage of the homozygous clone over time. This simple modeling could help to understand the effect of treatments on the JAK2V617F clonal structure without working at the unicellular level. Disclosures: No relevant conflicts of interest to declare.

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Smalberg, Jasper H., Edith Koehler, Sarwa Darwish Murad, Aurelie Plessier, Susana Seijo, Jonel Trebicka, Massimo Primignani et al. "The JAK2 46/1 haplotype in Budd-Chiari syndrome and portal vein thrombosis". Blood 117, n.º 15 (14 de abril de 2011): 3968–73. http://dx.doi.org/10.1182/blood-2010-11-319087.

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Abstract The germline JAK2 46/1 haplotype has been associated with the development of JAK2V617F-positive as well as JAK2V617F-negative myeloproliferative neoplasms (MPNs). In this study we examined the role of the 46/1 haplotype in the etiology and clinical presentation of patients with splanchnic vein thrombosis (SVT), in which MPNs are the most prominent underlying etiological factor. The single-nucleotide polymorphism rs12343867, which tags 46/1, was genotyped in 199 SVT patients. The 46/1 haplotype was overrepresented in JAK2V617F-positive SVT patients compared with controls (P < .01). Prevalence of the 46/1 haplotype in JAK2V617F-negative SVT patients did not differ from prevalence in the controls. However, JAK2V617F-negative SVT patients with a proven MPN also exhibited an increased frequency of the 46/1 haplotype (P = .06). Interestingly, 46/1 was associated with increased erythropoiesis in JAK2V617F-negative SVT patients. We conclude that the 46/1 haplotype is associated with the development of JAK2V617F-positive SVT. In addition, our findings in JAK2V617F-negative SVT patients indicate an important role for the 46/1 haplotype in the etiology and diagnosis of SVT-related MPNs, independent of JAK2V617F, that requires further exploration.

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23

Liang, Der-Cherng, Lee-Yung Shih, Chein-Fuang Huang, Chang-Liang Lai, Ya-Tzu Chang, Tung-Huei Lin, Jin-Hou Wu et al. "Different Cooperating Mutation Patterns of Receptor Tyrosine Kinases/Ras/JAK2 between De Novo AML1-ETO and CBFβ-MYH11 Acute Myeloid Leukemia." Blood 110, n.º 11 (16 de noviembre de 2007): 3487. http://dx.doi.org/10.1182/blood.v110.11.3487.3487.

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Abstract Background. Two-hit model of leukemogenesis has been proposed for AML; class I mutations that drive proliferation and survival, and class II mutations that block differentiation. Core-binding factor (CBF) AML consists of AML with AML1-ETO and AML with CBFβ-MYH11, that are class II mutations. Aim. We sought to determine the frequencies of cooperating mutations of class I including receptor tyrosine kinases (RTK)/Ras/JAK2 signaling pathways in CBF-AML, and to compare the patterns of cooperating mutations between AML with AML1-ETO and AML with CBFβ-MYH11. Patients and methods. By RT-PCR analysis, 130 adult and 45 children were identified to have CBF-AML, 129 with AML1-ETO and 46 with CBFβ-MYH11. Bone marrow samples at diagnosis were analyzed for FLT3-LM, FLT3-TKD, c-KIT, c-FMS, N-ras, K-ras and JAK2 mutations. Results. Sixty-six of 129 patients (51.2%) with AML1-ETO had RTK/Ras/JAK2 mutations compared with 30 of 46 patients (65.2%) with CBFβ-MYH11 (p=0.121). The frequencies of RTK/Ras/JAK2 mutations in 129 AML1-ETO AML were 3.9% (n=5) for FLT3-LM, 6.2% (n=8) for FLT3-TKD, 2.3% (n=3) for N-ras, 3.9% (n=5) for K-ras, 35.7% (n=46) for c-KIT, and1.6% (n=2) for JAK2 mutation. The frequencies of RTK/Ras/JAK2 mutations in 46 CBFβ-MYH11 AML were 2.2% (n=1) for FLT3-LM, 19.6% (n=9) for FLT3-TKD, 21.7% (n=10) for N-ras, 23.9% (n=11) for c-KIT, and none for K-ras or JAK2 mutations. No c-FMS mutations were detected in both subtypes of CBF-AML. All RTK/Ras/JAK2 mutations were mutually exclusive except three, one each with N-ras and K-ras mutations, FLT3-TKD and c-KIT mutations, c-KIT and JAK2 mutations, respectively. Patients with CBFβ-MYH11 had a significantly higher frequency of FLT3-TKD and N-ras mutations than patients with AML1-ETO (p=0.017 for FLT3-TKD, and p<0.001 for N-ras). Taken together, c-KIT mutations accounted for 32.6% in CBF-AML, the frequency of c-KIT mutations in patients with AML1-ETO was significantly higher than that of CBFβ-MYH11 subtype. Of the 46 patients with AML1-ETO and c-KIT mutations, 34 had mutations located at kinase domain (exon 17), 7 in exon 8, 1 in exon 9, and 4 in exon 11. Of the 11 patients with CBFβ-MYH11 and c-KIT mutations, 5 had mutations in exon 8, 2 in exon 11 and 4 in exon 17. Patients with AML1-ETO were more frequently associated with c-KIT mutations at kinase domain compared with patients with CBFβ-MYH11 (p=0.031), whereas those with CBFβ-MYH11 had a higher frequency of c-KIT mutations in exon 8 than patients with AML1-ETO (p=0.042). Conclusion. Our results showed that occurrence of cooperating mutations of RTK/Ras/JAK2 pathways are common in patients with CBF-AML, but the patterns of mutations were different between AML1-ETO and CBFβ-MYH11 subtypes.

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Zhang, Jinghui, Charles Mullighan, Richard Harvey, William L. Carroll, I.-Ming L. Chen, Meenakshi Devidas, Eric Larsen et al. "Lack of Somatic Sequence Mutations In Protein Tyrosine Kinase Genes Other Than the JAK Kinase Family In High Risk B-Precursor Childhood Acute Lymphoblastic Leukemia (ALL): A Report From the Children's Oncology Group (COG) High-Risk (HR) ALL TARGET Project". Blood 116, n.º 21 (19 de noviembre de 2010): 2752. http://dx.doi.org/10.1182/blood.v116.21.2752.2752.

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Abstract Abstract 2752 Introduction: We recently identified a poor prognostic subgroup of pediatric BCR-ABL1 negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1 positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Targeted sequencing revealed activating sequence mutations in the Janus tyrosine kinases (JAK1 (N=3), JAK2 (N=17) and JAK3 (N=1)) in 21 of 187 (11.2%) BCR-ABL1 negative, high-risk pediatric ALL cases. All 21 cases with JAK mutations had the BCR-ABL1-like expression profile, accounting for about 50% of the cases with this phenotype, suggesting that mutations in JAK kinases account for some, but not all, cases with this distinctive profile. To determine whether mutations in other kinases might also be associated with this distinctive gene expression profile, we sequenced 126 genes encoding tyrosine kinases and mediators of kinase signaling in an additional 46 high-risk ALL cases with a BCR-ABL1-like expression profile. The genes sequenced included the entire tyrosine kinome. Methods: The 46 leukemia specimens studied were from patients enrolled on COG clinical trials for high risk ALL (P9906, n=23 and AALL0232, n=23), with risk defined primarily by elevated WBC and/or age > 10 years. All 46 cases had a BCR-ABL1 like expression profile. The 23 P9906 cases all lacked JAK mutations, while 3 of the 23 AALL0232 cases were found to have activating JAK mutations (JAK1 (N=1), JAK2 (N=2)). The entire coding region and UTRs of each gene was amplified by PCR of whole genome amplified genomic DNA, and subjected to Sanger sequencing. A CEPH sample (NA19085) was also included as a normal control DNA. Results: A total of 1,149,117 bases were sequenced bi-directionally for each sample; 96% of the targeted bases were covered with high-quality sequencing data. We identified a total of 2,302 variations predicted to change protein sequences, 173 of which are novel, putative variations after removing germline variations found in dbSNP, The Cancer Genome Atlas Project (TCGA) and the normal CEPH sample NA19085 in this study. For each novel variation, the tumor DNA was resequenced and matching normal DNA was sequenced to validate the original observation and to distinguish somatic from inherited variants. The results show that 105 variations are germline, 20 are false positives while the remaining markers failed in validation assay. Aside from 1 FLT3 mutation (23aainsN609), there are no confirmed somatic mutations in any other tyrosine kinase genes. Conclusion: Aside from JAK mutations, somatically acquired sequence mutations in tyrosine kinase genes are rare in children with high risk ALL and BCR-ABL1 like gene expression profiles. We are pursuing the identification of alternative mechanisms for kinase activation that might explain the distinctive expression profile observed in these cases. Disclosures: Relling: St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding. Hunger:bristol myers squibb: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Mahmood, Shameem, Louise Mellish, Nicholas Lea, Austin G. Kulasekararaj, Atiyeh Abdallah, Sivatharsny Srirangan y Ghulam J. Mufti. "The JAK2 46/1 Haplotype Analysis In Essential Thrombocythaemia and Polycythaemia Rubra Vera Reveals That CC Genotype Is Associated with a Higher JAK2V617F and c-MPL W515 Allele Burden". Blood 116, n.º 21 (19 de noviembre de 2010): 1977. http://dx.doi.org/10.1182/blood.v116.21.1977.1977.

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Abstract Abstract 1977 First 2 authors contributed equally. Background: Genomic-wide association studies have identified the germline 46/1 haplotype as a predisposing allele associated with JAK2V617F positive myeloproliferative neoplasms (MPN). The present study analysed data on 856 JAK2V617F positive patients, 326 of which had complete clinical data. Aims: To evaluate the JAK2 46/1 haplotype frequencies, JAK2V617F allele burden, c-MPL 515 mutation and risk of transformation. Methods: Genomic DNA from whole peripheral blood or bone marrow patient samples was analysed as follows: JAK2V617F allele burden by Q-PCR, JAK2 exon 12 mutations by Q-PCR and PCR fragment analysis, MPL W515 L and K mutations by allele specific PCR. The 46/1 JAK2 mutation susceptibility haplotype (46/1) tagging SNP rs12343867 (susceptibility allele C) were analysed by pyrosequencing. Results: The allele frequency for the 46/1 tag SNP rs1234867 in the 856 patients was calculated for the total JAK2V617F cohort (0.48) and the clinical entities ET (0.34) and PRV (0.44) confirming that the 46/1 haplotype is greatly over represented in JAK2V617F MPD patients as compared to published the control population (Wellcome Trust Case Control Consortium (WTCCC) (0.24). The Analysis of the 856 patients demonstrated that JAK2V617F and c-MPL W515L/K mutations co-existed in 16 patients(1.9%), the incidence of c-MPL W515L being twice as common as the c-MPL W515K mutations. There was no correlation between these mutations and age or 46/1 haplotype status. The JAK2V617F allele burden (AB) was lower in the c-MPL mutant patients, the average JAK2AB 31%. 3 out 4 c-MPL patients for which clinical information was available had a diagnosis of ET. No JAK2 exon 12 mutations were found in any of the 859 JAK2V617F positive samples suggesting that co-existing JAK2 exon 14 and exon 12 mutations are extremely rare. The genotypic data in ET patients showed: C/C 12%, C/T 44%, T/T 44% and their respective JAK2V617 allele burden (AB) were 46%, 32%, 29%. The genotype data in PRV patients: C/C 18%, C/T 53%, T/T 28.6% and their respective AB were 47%, 31% and 39%. The median AB was 32% (n=121) for ET and 37% (n=103) for PRV. Within a cohort of 255 patients (ET=138, PRV=117) 4% of ET and 6% of PRV patients transformed to acute myeloid leukaemia or myelofibrosis with no predominant haplotype association. In the ET patients, the median AB was 35%, there was no significant difference in the JAK2 V617F AB between those who transformed or not (p=0.45). Interestingly, on the whole ET group C/C genotype patients were more likely to have an allele burden >50% (p=0.058). In the PRV patients, the median AB was 48%. Again, the C/C genotype, PRV patients were more likely to have an AB>50% (p=0.06), although not reaching statistical significance. Conclusions: The 46/1 haplotype in both clinical entities ET and PRV demonstrated a higher allele burden in the C/C genotype in comparison to the other genotypes. No predominant haplotype predicted the risk of transformation to a more aggressive disease such as MF or AML. The analysis also showed that c-MPL W515K/L mutations can co-exist with JAK2V617F. The c-MPL W515K/L mutations did not exhibit a positive correlation with a preferential 46/1, but was associated with a lower allele burden. No co-existing exon 12 and exon 14 mutations were found, suggesting the rarity of this occurrence. Disclosures: No relevant conflicts of interest to declare.

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Campiotti, Leonardo, Lorenzo Elli, Matteo B. Suter, Luigina Guasti y Francesco Pallotti. "JAK2, 46/1 haplotype and chronic myelogenous leukemia: diagnostic and therapeutic potential". Clinical Chemistry and Laboratory Medicine (CCLM) 58, n.º 1 (18 de diciembre de 2019): e24-e26. http://dx.doi.org/10.1515/cclm-2019-0158.

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Andrikovics, H., S. Nahajevszky, M. Koszarska, N. Meggyesi, A. Bors, G. Halm, S. Lueff et al. "JAK2 46/1 haplotype analysis in myeloproliferative neoplasms and acute myeloid leukemia". Leukemia 24, n.º 10 (2 de septiembre de 2010): 1809–13. http://dx.doi.org/10.1038/leu.2010.172.

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28

Bellanne-Chantelot, Christine, Myriam Labopin, Isabelle Chaumarel, Francois Delhommeau, Gwendoline Leroy, Florence Bellanger, Gilles Thomas, William Vainchenker y Albert Najman. "Heterogeneous Distribution of the JAK2 Val617Phe Activating Mutation in Familial Myeloproliferative Disorders." Blood 106, n.º 11 (16 de noviembre de 2005): 115. http://dx.doi.org/10.1182/blood.v106.11.115.115.

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Abstract An activating mutation Val617Phe of the tyrosine kinase JAK2 has recently been reported by several groups in the majority of patients with polycythemia vera (PV) and approximately half of those with either essential thrombocythemia (ET) or myelofibrosis with myeloid metaplasia (MMM). These haematological malignancies characterized by a stem cell-derived clonal proliferation of myeloid cells are traditionally subgrouped as myeloproliferative disorders (MPD). Until now, the JAK2 mutation has been described in sporadic cases of MPD but the prevalence of this mutation in familial MPD is unknown. Genomic DNA from peripheral blood mononuclear cells of 129 familial cases of MPD - 60 with PV, 61 with ET and 8 with MMM - were screened by sequencing for the JAK2 Val617Phe (1849 G>T) mutation. The mutant T allele was detected in 81 of 129 familial MPD: 45 (75%) with PV, 30 (50%) with ET and 6 (75%) with MMM. The T allele was the major allele (>50% of peak height) in 20% and 25% of patients with PV or MMM respectively compared to 8% in patients with ET. Moreover, 3 first degree relatives with endogenous erythroid colonies and with normal blood cell counts were also carriers of the JAK2 mutation. Then, we analysed the distribution of the JAK2 mutation in 46 families with at least 2 affected cases. In 20 (44%) families, all affected subjects were carriers of the JAK2 mutation. This subgroup included MPD families with homogeneous phenotype (60%) as well as MPD with mixed phenotypes (40%). In 7 (15%) other families including principally families with ET, the JAK2 mutation was not detected in any affected patients; all had the same haematological profile compared to positive-JAK2 patients. Interestingly, in the other 19 (41%) families, the distribution of the JAK2 mutation was heterogeneous consisting of at least one affected patient carrying the JAK2 mutation and one or two affected relatives without the JAK2 mutation. In these discordant families, the absence of the JAK2 mutation was not associated with a specific phenotype. A more severe expressivity of the disease or the occurence of complications were not observed in carriers of the JAK2 mutation. These results highlighted the heterogeneous distribution of JAK2 mutation in familial MPD and may suggest that JAK2 is not a major genetic predisposing factor. This hypothesis was confirmed by a genome-wide linkage analysis performed on the 46 families that excluded as a candidate region the short arm of chromosome 9 in which JAK2 gene is located. Finally, several groups have reported in sporadic cases the absence of the JAK2 mutation in T-cells and non-hematopoietic tissues showing that JAK2 mutation is an acquired myeloid lineage-specific mutation. Preliminary results on T-cells CD3+ and B-cells CD19+ sorted by flow cytometric analysis of peripheral blood from 20 unrelated patients with familial MPD were consistent with those previous results. In conclusion, the prevalence of the JAK2 mutation is similar in sporadic and familial cases of MPD. The observation of (i) a heterogeneous distribution of the JAK2 mutation within families and (ii) the absence of the JAK2 mutation in non myeloid cells corroborate the hypothesis that JAK2 mutation is a somatic event.

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Kouroupi, Eirini G., Bruno Cassinat, Aurelie Plessier, Sylvia Bellucci, Christine Chomienne, Bernard Granchamp, Dominique Valla y Jean-Jacques Kiladjian. "Lack of Association Between the 46/1 JAK2 Haplotype and the Presence of JAK2V617F Mutation In Splanchnic Vein Thrombosis Patients". Blood 116, n.º 21 (19 de noviembre de 2010): 4120. http://dx.doi.org/10.1182/blood.v116.21.4120.4120.

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Abstract Abstract 4120 Aim: The majority of myeloproliferative neoplasms (MPN), i.e. Polycythemia vera (PV), Essential Thrombocytemia (ET) and Primary Myelofibrosis, are characterized by the presence of the acquired JAK2V617F gene mutation. Recent studies revealed that the 46/1 or “GGCC” haplotype located in the JAK2 gene is strongly associated with the development of a JAK2V617F positive MPN. However, this particular haplotype was also detected in excess in JAK2V617F negative MPN carrying mutations across JAK2 exon 12 or the MPL gene, suggesting that this germline genetic variation increases the risk of developing a MPN regardless of the acquisition of one particular mutation. A MPN is found in approximately half of the patients presenting with Splanchnic Vein Thrombosis (SVT) and JAK2V617F mutation is present in virtually all of these MPN patients. In this study we sought to clarify the impact of the JAK2 46/1 haplotype on the susceptibility to SVT. Patients and Methods: Peripheral blood was obtained after informed consent; following DNA extraction we proceeded to genotyping using commercially available TaqMan SNP genotyping assays for one tag SNP (rs10974944) which is in complete linkage disequilibrium with the 46/1 haplotype. Results were confirmed using another tag SNP (rs1234867). The study was performed on 170 patients with SVT, 58 patients with peripheral vein thrombosis and 31 patients with JAK2V617F positive PV. Results: In the 170 patients with SVT the frequency of G-allele that stands for the 46/1 haplotype was 0.28 (CC n=89; C/G n=67; G/G n=14), not significantly different from that of the published population controls (n=1500) from the Welcome Trust Case Control Consortium WTCCC (0.24; p=0.11 by the Fisher exact test). The frequency of the 46/1 haplotype in 58 patients with peripheral vein thrombosis was also similar to that of the WTCCC (0.24). However, the frequency of the 46/1 haplotype in SVT patients was significantly different from its frequency in a group of 31 patients with JAK2V617F positive PV (0.52; p=0.0005). When we analysed SVT patients according to their JAK2 mutational status, we found no difference in the frequency of the 46/1 haplotype between the JAK2V617F positive patients (0.27; n=75) and the JAK2V617F negative patients (0.28; n=95) (p=0.90). Of note, a JAK2 allele burden greater than 50% was observed in 11% of patients with JAK2V617F positive SVT and 45% of patients with JAK2V617F positive PV. Conclusions: In this large cohort of 170 patients with SVT the frequency of the 46/1 haplotype was not different from the cohort of controls of the WTCCC. This result suggests that the 46/1 haplotype is not a susceptibility locus for the development of SVT. Moreover, this haplotype was not overrepresented in the group of SVT patients harbouring a JAK2V617F mutation compared to JAK2V617F negative patients. This result is in apparent contradiction with the hypothesis that the 46/1 haplotype predisposes to the acquisition of JAK2V617F mutation or of a MPN, in agreement with recent studies reporting almost identical 46/1 frequencies between V617F-negative patients and V617F-positive patients with low mutation burden (i.e. <50%), which is the case of SVT patients in this series. Disclosures: No relevant conflicts of interest to declare.

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30

Ahn, Jeong Yeal, Pil Whan Park, Yiel Hea Seo, Dong-Bok Shin, Jae-Hoon Lee, Soo-Jin Yoo y Soo-Mee Bang. "JAK2 V617F Mutation in Essential Thrombocythemia." Blood 108, n.º 11 (16 de noviembre de 2006): 4925. http://dx.doi.org/10.1182/blood.v108.11.4925.4925.

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Abstract Background: Essential thrombocythemia (ET) is thought to reflect transformation of a multipotent hematopoietic stem cell, but its molecular pathogenesis has remained obscure. But tyrosine kinase, especially Janus kinase 2 (JAK2) has been implicated in myeloproliferative disorders other than chronic myeloid leukemia. We investigated the incidence and its correlation with other clinicopathologic variables of JAK2 mutation in patients with ET and reactive thrombocytosis (RT). Method: JAK2 mutation analysis, using allele-specific polymerase chain reaction, was undertaken on genomic DNA from bone marrow aspirates of 24 patients with ET and peripheral blood in 36 patients with RT. Results: JAK2 mutation was detected in 11 patients (46%) among the 24 patients with ET and was not found in 36 patients with RT. In patients with ET, older age and leukocytosis were related with JAK2 mutation without statistical significance (p=0.172 and 0.094, respectively). But this mutation was not correlated with sex, hemoglobin, platelet count, splenomegaly, increased cellularity of bone marrow, bone marrow fibrosis and vascular complications. Conclusions: The current observation strengthens the specific association between JAK2 mutation and ET. At the diagnosis of ET, identification of JAK2 mutation should be incorporated in foundation for new approaches.

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Hasan, Salma, Bruno Cassinat, Jean-Pierre Le Couédic, Fabrizia Favale, Barbara Monte-Mor, Catherine Lacout, Eric Solary et al. "Use Of 46/1 Haplotype Permits To Follow JAK2V617F Clonal Architecture In PV Patients: Clonal Evolution and Impact Of IFNα Treatment". Blood 122, n.º 21 (15 de noviembre de 2013): 4109. http://dx.doi.org/10.1182/blood.v122.21.4109.4109.

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Abstract Somatic V617F oncogenic mutation of the protein kinase JAK2 is the most prevalent genetic abnormality in the three myeloproliferative neoplasms (MPNs), namely polycythemia vera (PV, 95%), essential thrombocythemia (ET, 55%) and myelofibrosis (MF, 50%). About 30% of PV patients are homozygous for this mutation due to mitotic homologous recombination (HR). JAK2 46/1 haplotype is strongly associated with the cis-aquisition of JAK2V617F mutation. Since, HR involves most of 46/1 haplotype, JAK2V617F and 46/1 tagging SNPs are also reduced to homozygosity. We hypothesized that 46/1 tagging SNPs, which are in complete linkage disequilibrium with JAK2, can serve as a measure of JAK2V617F homozygosity. 46/1 allele burden (X%) can be used to calculate the HR (HR%) that is a measure of JAK2V617F/V617F clones [(X%-50%)x2]. JAK2V617F/V617F frequency and JAK2V617F allele burden (Y%) can be then exploited to calculate the frequency of JAK2V617F/WT [(Y%-RH%)x2] and JAK2WT [100-(JAK2V617F/WT%+ JAK2V617F/V617F)] clones. The purpose of this study was to calculate the clonal frequency of WT, JAK2V617F/WT and JAK2V617F/V617F in progenitors compartments of PV patients. Here, we have dissected the JAK2V617F clonal architecture in 9 PV patients heterozygous for the 46/1 haplotype. First, we measured the global JAK2V617F and 46/1 allele burden in CD34+ cells either by allele-specific PCR or by Ion Torrent sequencing in order to calculate the expected WT, JAK2V617F/WT and JAK2V617F/V617F clones. Next, we compared thees results with the experimental clonal frequency of WT, JAK2V617F/WT and JAK2V617F/V617F clones in individual colonies derived from the CD34+CD38+ compartment. This algorithm was validated in majority of patients. Moreover, we have exploited this formula to the terminally differentiated polynuclear neutrophils (PNN) and found that JAK2V617F/V617Fclones acquire strong amplification during differentiation. Finally, we used this model to assess the therapeutic potential of IFNα in a cohort of 15 PV patients. IFNα exposure resulted in more impressive and rapid decrease of JAK2V617F allele burden of pure JAK2V617F homozygous patients than in pure JAK2V617F heterozygous patients. Calculations revealed this decrease in JAK2V617F is due to preferential targeting of JAK2V617F/V617Fclones in responding patients. These results demonstrate that JAK2 46/1 haplotype can be used to estimate JAK2V617F clonal architecture in PV patients. This simple modeling can be useful to follow the efficacy and specificity of treatment on JAK2V617F clones in MPNs, without needing exploration at the unicellular level. In addition, it suggests that IFNα treatment more specifically targets the JAK2V617F/V617F clone in responding patients. Disclosures: No relevant conflicts of interest to declare.

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Lea, Nicholas C., Lara N. Roberts, Raj K. Patel, Rachel Westbrook, Michael A. Heneghan, Azim M. Mohamedali, Alex E. Smith et al. "Prevalence of 46/1 JAK2 Haplotype in Patients with Budd-Chiari Syndrome with and without JAK2V617F and TET2 Mutations." Blood 114, n.º 22 (20 de noviembre de 2009): 434. http://dx.doi.org/10.1182/blood.v114.22.434.434.

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Abstract Abstract 434 Budd-Chiari Syndrome (BCS) is a group of disorders resulting from obstruction to hepatic venous outflow; myeloproliferative disorder (MPD) accounts for 10-40% of cases. We previously described latent MPD in 58.5% of patients with idiopathic BCS, detected with allele-specific PCR for the JAK2V617F mutation and proposed its use as a screening tool for occult MPD. A predisposing germline JAK2 haplotype (designated 46/1) has since been described as a strong genetic risk factor for MPD and may further characterise latent MPD in BCS. We studied 28 patients with BCS (23 from our original cohort; female n=16, mean age 30.3 years, SD 10) presenting between 1985 and 2008; 14 with the JAK2V617F mutation. Genomic DNA was obtained from archived bone marrow films, fractionated and unfractionated peripheral blood or bone marrow leucocytes. Skin biopsy or CD3+ cells were used as a source of constitutional DNA. DNA was analysed by pyrosequencing for 2 SNPs (rs12340895, rs12343867) which tag the 46/1 JAK2 haplotype. The 46/1 haplotype was detected in 16/28 (57.1%) subjects; 50% of those with the JAK2V617F mutation and 64.3% of those without it. The prevalence in those lacking the JAK2V617F mutation is significantly higher than the frequency in the Wellcome Trust Case Control Consortium cohort of 24% (P=0.0023). 3/28 subjects had previously diagnosed JAK2V617F positive Polycythemia Vera (PV) and all had the 46/1 haplotype, resulting in a prevalence of 36.4% in those with JAK2V617F positive latent MPD. Age at presentation of BCS was significantly lower in those with the 46/1 haplotype (26.4 years compared to 34.8 years, P=0.03). This difference remained significant in those lacking the JAK2V617F mutation (24.0 years compared to 37.6 years, P=0.024) but was not seen in those with the JAK2V617F mutation (P=0.547). There was no difference in presenting clinical features, haematological parameters or treatment between those with and without the 46/1 haplotype. Overall survival in 26/28 patients was 76.9% (median 90 months, range 2 days to 266 months). 17/28 subjects underwent OLT of which 14/17 (11/12 with 46/1 haplotype) are alive at a median of 90 months post transplant (range 9-266 months). 3/17 patients developed post-OLT veno-occlusive disease, all with the JAK2V617F mutation and 2/3 with the 46/1 haplotype. Overt MPD has not developed in any patient without the JAK2V617F mutation; repeat JAK2 mutational analysis was undertaken in 3/14 (2/3 with 46/1 haplotype) and none have acquired the mutation at a mean of 54 months. 19/28 cases were genotyped using SNP markers (Affymetrix SNP6); 3/19 have acquired uniparental disomy (aUPD) on 9p overlapping the JAK2 gene. As TET2 has been postulated as a ‘pre-JAK2' aberration, we sequenced the complete TET2 gene using massively parallel high throughput sequencing (Roche 454); 2/15 patients samples were positive for TET2 mutations. One of our cases had a familial history of PV; the patient, his father and uncle all have JAK2V617F positive PV and were heterozygous for the 46/1 haplotype in DNA extracted from a skin biopsy. 2/3 were homozygous for both the 46/1 haplotype and JAK2V617F mutation in bone marrow granulocytes with SNP6 array data confirming aUPD on 9p. JAK2V617F was detected in cultured in vitro colonies from all 3 family members. All 3 affected family members had normal cytogenetics and normal TET2 gene. 3 unaffected siblings were heterozygous for the 46/1 haplotype both in peripheral blood, CD3+ cells and granulocytes but negative for JAK2V617F mutation and lacked aUPD on 9p. We have found a highly significant prevalence of the 46/1 haplotype in our cohort of BCS, as well as in family members of a patient with JAK2V617F positive BCS and PV. The 46/1 haplotype was detected in patients with idiopathic BCS with and without the JAK2V617F mutation, suggesting a predisposition to idiopathic BCS independent of JAK2V617F mutation acquisition and latent MPD. The prevalence and lower age of presentation in those with the 46/1 haplotype lacking the JAK2V617F mutation supports an alternate, as yet unknown, mechanism predisposing to BCS. The presence of the 46/1 haplotype in unaffected relatives of our JAK2V617F BCS patient suggests that additional germline variation may predispose to or protect from acquisition of JAK2V617F positive disease. Alternatively the 46/1 haplotype may directly confer a cellular growth advantage via increased responsiveness of JAK2 to cytokine stimulation. Disclosures: No relevant conflicts of interest to declare.

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Paes, Jhemerson, George A. V. Silva, Andréa M. Tarragô y Lucivana P. de Souza Mourão. "The Contribution of JAK2 46/1 Haplotype in the Predisposition to Myeloproliferative Neoplasms". International Journal of Molecular Sciences 23, n.º 20 (20 de octubre de 2022): 12582. http://dx.doi.org/10.3390/ijms232012582.

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Haplotype 46/1 (GGCC) consists of a set of genetic variations distributed along chromosome 9p.24.1, which extend from the Janus Kinase 2 gene to Insulin like 4. Marked by four jointly inherited variants (rs3780367, rs10974944, rs12343867, and rs1159782), this haplotype has a strong association with the development of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) because it precedes the acquisition of the JAK2V617F variant, a common genetic alteration in individuals with these hematological malignancies. It is also described as one of the factors that increases the risk of familial MPNs by more than five times, 46/1 is associated with events related to inflammatory dysregulation, splenomegaly, splanchnic vein thrombosis, Budd–Chiari syndrome, increases in RBC count, platelets, leukocytes, hematocrit, and hemoglobin, which are characteristic of MPNs, as well as other findings that are still being elucidated and which are of great interest for the etiopathological understanding of these hematological neoplasms. Considering these factors, the present review aims to describe the main findings and discussions involving the 46/1 haplotype, and highlights the molecular and immunological aspects and their relevance as a tool for clinical practice and investigation of familial cases.

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Ma, Wanlong, Hagop Kantarjian, XI Zhang, Xiuqiang Wang, Zhong Zhang, Chen-Hsiung Yeh, Anthony Sferruzza, Susan O'Brien y Maher Albitar. "Splice Variant JAK2 Transcript Deleting Exon 14 in Patients with Chronic Myeloproliferative Neoplasms." Blood 114, n.º 22 (20 de noviembre de 2009): 2161. http://dx.doi.org/10.1182/blood.v114.22.2161.2161.

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Abstract Abstract 2161 Poster Board II-138 The JAK2 V617F mutation in exon 14 is the most common mutation in chronic myeloproliferative neoplasms (MPNs). While other point mutations and small deletions and insertions in exons 12, 13, and 14 have been reported in the JAK2 JH2 domain, deletion of the entire exon 14 is rarely detected in patients with MPNs. In a series of >10,000 samples from patients with suspected MPNs tested for JAK2 mutations by direct sequencing of mRNA, we detected a complete exon 14 (88 bp) deletion mutation in <1% of those with JAK2 mutation. This appears to be an alternative splicing mutation, not detectable with DNA-based testing, leading to a frameshift deletion in the JAK2 JH2 domain and the expression of a truncated protein (S593I fsX8). Although this mutation was present at detectable levels (>15% of total JAK2 transcript) in a small proportion of MPN cases, we decided to investigate the possibility it may be expressed at low levels (<15% of JAK2 transcript) in patients with MPNs. Using a sensitive reverse transcription-PCR—based fluorescent fragment analysis method to quantify the percentage of truncated (minus exon 14) JAK2 mRNA as compared to wild-type, we tested 61 patients with confirmed MPN; 183 patients with suspected MPNs (93 V617F positive, 90 V617F negative); and 46 healthy normal control subjects. The wild-type PCR product was 273 bp, while the exon 14 splice mutant displayed a 185-bp peak. All samples with a splicing mutant expression to wild-type ratio >15% were confirmed by direct sequencing. The JAK2 exon 14 splice mutation was detected at low levels in 9 of the 61 MPN patients (15%), accounting for 3.96% to 33.85% (mean=12.04%) of JAK2 transcript in these individuals. Among the 183 suspected MPN patients, the exon 14 splice variant was detected in 20 of the 93 (21.5%) with V617F (mean expression level relative to wild type=5.41%, range=2.13%-26.22%) and 31 of the 90 (34.4%) without V617F (mean expression=3.88%; range=2.08%-12.22%). All 46 normal individuals were considered negative for the alternatively spliced transcript. In conclusion, the expression of an alternatively spliced JAK2 mRNA with deletion of exon 14, leading to a truncated JAK2 protein, is a common abnormality in patients with MPNs. This alternatively spliced transcript is more common in MPN patients without V617F mutation and might contribute to the leukemogenesis in these patients. Low levels of JAK2 exon 14 splice mutation may also contribute to the effects of the V617F mutation in patients with MPNs. However, this mutation is missed if DNA and not the RNA is used for testing for JAK2 mutations. Disclosures: No relevant conflicts of interest to declare.

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Dias, Daniela Ferreira, Marcelo Bellesso, Rodrigo Santucci, Renata Campos Elias, Veronica Ramos Oliveira, Renato Centrone y Adelson Alves. "Myeloproliferative Neoplasm with BCR-JAK2 Fusion Gene As the Result of t(9;22)(p24,11.2) in a Brazilian Patient". Blood 120, n.º 21 (16 de noviembre de 2012): 4808. http://dx.doi.org/10.1182/blood.v120.21.4808.4808.

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Abstract Abstract 4808 Introduction Chronic Myeloid Leukemia (CML) is the most well described disease result of t(9;22)(q34,q11.2). This chromosomal rearrangement leads to well-know BCR-ABL fusion that promotes tyrosine kinase activity. There are others oncogenic BCR fusion found such as PDGFRA (4q12), FGFR1(8p12) that causes myeloproliferative disorders (MD). JAK2 gene is one of the 4 genes members of JAK family. The JAK2 V617F mutation which results from a G –>T transversion at nucleotide 1849 in exon 14 of the JAK2 gene, the consequence of which is substitution of valine by phenylalanine at codon 617 is associated with MD and it is a major diagnosis criterion for Primary Myeloficrosis, Polycythaemia vera and Essential thrombocytemia. There are described a lot chromosomal translocations involving the JAK2 locus. We report an extremely rare case with BCR-JAK2 fusion gene as the result of t(9;22)(p24,q11.2) for the first time in Brazilian people, and it is the 6thcase all of the world. Case Report In April 2010, a 54 years old male patient presented fatigue, abdominal pain and splenomegaly. A blood count revealed leukocytosis 93.380/mm3 with a predominance of neutrophils and left shift. Conventional cytogenetic analysis was performed and it was evidenced 46,XY, t(9;22)(p24;q11.2) in 90% metaphases examined, due to expected association it was promoted BCR-ABL1 fusion gene and it was not detected by using RT-PCR. He was treated with imatinib 400mg/day because the involvement of BCR gene. After three months he presented weight loss, progressive splenomegaly without hematologic response and it was modified to Dasatinib 150mg/day plus hydroxyureia 3g/day. In August 2011, due to not hematologic response, it was stopped Dasatinib treatment and nowadays patient has been treating with hydroxyureia 1.5g/day. His last follow up in May 2012, blood count was abnormal Hb 16.8g/dl leukocytes 7730/mm3 and low platelets count 32.000/mm3. The differential count showed 65.3% segmented granulocytes, 13.6% eosinophlis, 1.6% basophil, 2.6% monocytes, 16.9% lymphocytes. It was repeated conventional Karyotyping and it was evidenced 46,XY, t(9;22)(p24;q11.2) in all of metaphases examined. The presence of BCR-ABL rearrangement was excluded by using the fluorescence in situ hybridization (FISH) using a BCR-ABL probe. In addition, it was not evidenced FIP1L1-PDGFRa fusion gene and JAK2 V617F mutation by using RT-PCR. Discussion We have described a male patient with MD with t(9;22)(p24;q11.2) wich leads to the BCR-JAK2 fusion and it was not evidenced BCR-ABL1, FIP1L1-PDGFRa fusion genes and JAK2 V617F mutation by using RT-PCR. Moreover, patient has not been achieved hematologic response with tyrosine kinase inhibitors: imatinib and dasatinib. In the five cases reported three presented MD, one Acute Myeloid Leukemia and one Acute Lymphoblastic Leukemia. Only in one case report it was prescribed imatinib and the patient lost the follow up (Table1). The BCR-JAK2 fusion protein contain the coiled-coil dimerization domain of BCR and the protein tyrosine Kinase domain (JH1) of JAK2. It was not possible to define what would be the best therapy, because tyrosine kinase inhibitors may not be effective to the BCR-JAK2 fusion. Maybe in MD presentation, we could return to pre- tyrosine kinase inhibitors era based on treatments with hydroxyureia, subcutaneous cytarabine and interferon for patients that were not potential candidates for allogeneic transplant. Disclosures: No relevant conflicts of interest to declare.

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Shi, Ce, Lina Han, Yoko Tabe, Hong Mu, Shuo-Chieh Wu, Jin Zhou, Zhihong Zeng et al. "Dual Targeting of JAK2 Signaling with a Type II JAK2 Inhibitor and of mTOR with a TOR Kinase Inhibitor Induces Apoptosis in CRLF2-Rearranged Ph-like Acute Lymphoblastic Leukemia". Blood 124, n.º 21 (6 de diciembre de 2014): 3706. http://dx.doi.org/10.1182/blood.v124.21.3706.3706.

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Abstract Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subtype of high-risk B-precursor ALL (B-ALL) that carries a high risk of relapse after conventional chemotherapy (Mullighan et al, N Engl J Med. 2009). Rearrangements in CRLF2, leading to overexpression of the receptor for the cytokine thymic stromal lymphopoietin (TSLP), are present in approximately 50% of Ph-like ALLs and are associated with hyperactive JAK/STAT and PI3K/mTOR signaling (Harvey et al, Blood 2010; Tasian et al, Blood 2014). Previous studies established that combining a tyrosine kinase inhibitor (TKI) with an mTOR inhibitor provides greater anti-leukemia efficacy than a TKI alone in Ph+ B-ALL (Janes et al, Nat. Med. 2013). While allosteric mTOR inhibitors such as rapamycin only partially block mTORC1 and do not directly inhibit mTORC2, second-generation ATP-competitive mTOR kinase inhibitors (TOR-KIs) efficiently block both mTOR outputs and show greater efficacy when combined with TKIs. In this study, we investigated anti-leukemia efficacy and intracellular signaling networks in Ph-like CRLF2+ ALL models treated with combinations of a type I or type II JAK-2 inhibitor and a TOR-KI. The inhibitors were tested in human B-precursor Ph-like ALL cell lines MUTZ5 (IGH@-CRLF2 translocation, JAK2 R683G mutation) and MHH-CALL-4 (IGH@-CRLF2 translocation, JAK2 I682F mutation), B-ALL cell line REH (CRLF2wt), and primary CRLF2+ xenograft cells in vitro. For signaling and growth inhibition studies, cells were stimulated with 25 ng IL-7 or TSLP for 30 min, then with JAK2 type I inhibitor ruxolitinib (500nM) or type II inhibitor NVP-BBT594 (500nM) (Andraos et al., Cancer Discov. 2012) and allosteric mTOR inhibitor rapamycin or TOR-KI AZD2014. Effects on intracellular signaling were determined by phospho-flow cytometry. Anti-leukemia effects were characterized by viable cell counts and annexin V flow cytometry. In vitro stimulation of CRLF2-rearranged cells with TSLP robustly induced JAK/STAT signaling (p-JAK2(Tyr1008), p-STAT5(Ty694)) and AKT/pS6 signaling (p-AKT(Ser473), p-rS6(S235/236) (Fig. 1A). Stimulation with IL-7, mimicking support by the normal bone marrow environment, induced a lesser degree of activation of these phospho-proteins, except for p-4EBP1(T37/46), which was constitutively highly expressed in these cells and further induced by IL-7. These findings warranted combination studies of JAK2 and mTOR inhibitors. JAK2 inhibition with ruxolitinib or BBT594 efficiently inhibited TLSP-induced STAT5, AKT, and S6 activation, yet failed to decrease p-4EBP1 (Fig. 1A). AZD2014 but not rapamycin fully inhibited p-4EBP1, consistent with efficient inhibition of TORC1, and caused profound cell cycle arrest and growth arrest in CRLF2+ cells (Fig. 1A, C). In turn, combination of ruxolitinib and AZD2014 further reduced cell proliferation but did not induce apoptotic cell death (Fig. 1B, D). Recent studies indicate persistence of JAK2-mutated cells in myeloproliferative neoplasms upon long-term exposure to a type I JAK2 inhibitor, mediated by JAK2 heterodimerization and reactivation of JAK-STAT signaling (Koppikar et al., Nature 2012). We therefore compared the in vitro efficacy of ruxolitinib and BBT594, a type II JAK2 inhibitor that retains the ability to bind inactive JAK2, in Ph-like ALL cells. In MUTZ-5 but not in MHH-CALL-4 cells, ruxolitinib increased JAK2 activation loop phosphorylation (p-JAK2-Tyr1008) despite suppression of STAT5 phosphorylation; in contrast, BBT594 diminished both p-JAK2 and p-STAT5. Unexpectedly, BBT594 induced apoptotic cell death in both MUTZ5, MHH-CALL-4 (Fig 1B) and in ALL blasts recovered from primary CRLF2+ xenograft and grown in OP9 in vitro co-culture; the combination of BBT594 with AZD2014 increased apoptosis and reduced cell viability even further, in both cell lines and in stroma-attached primary ALL cells. In summary, these results suggest that efficient blockade of JAK2/STAT5 with a type II JAK2 inhibitor translates into cell death of JAK2-addicted CRLF2-rearranged cells and may have the capacity to eliminate JAK2-mutated clones. Concomitant blockade of TORC1 signaling with a TOR-KI reduces B-ALL cell proliferation through potent inhibition of 4EBP1 and causes synthetic lethality, providing avenues for novel, rationally designed combinatorial regimens in this subset of Ph-like B-ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Wang, Hui, Guixiang Sun, Peijin Zhang, Jing Zhang, Er Gui, Maoheng Zu, Enzhi Jia et al. "JAK2 V617F mutation and 46/1 haplotype in Chinese Budd-Chiari syndrome patients". Journal of Gastroenterology and Hepatology 29, n.º 1 (19 de diciembre de 2013): 208–14. http://dx.doi.org/10.1111/jgh.12379.

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Zerjavic, Katja, Boris Zagradisnik, Lidija Lokar, Marjana G. Krasevac y Nadja K. Vokac. "The association of the JAK2 46/1 haplotype with non-splanchnic venous thrombosis". Thrombosis Research 132, n.º 2 (agosto de 2013): e86-e93. http://dx.doi.org/10.1016/j.thromres.2013.06.021.

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Soler, G., A. Bernal-Vicente, A. I. Antón, J. M. Torregrosa, E. Caparrós-Pérez, I. Sánchez-Serrano, A. Martínez-Pérez, B. Sánchez-Vega, V. Vicente y F. Ferrer-Marin. "The JAK2 46/1 haplotype does not predispose to CALR-mutated myeloproliferative neoplasms". Annals of Hematology 94, n.º 5 (9 de diciembre de 2014): 789–94. http://dx.doi.org/10.1007/s00277-014-2266-y.

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Guglielmelli, P., F. Biamonte, A. Spolverini, L. Pieri, A. Isgrò, E. Antonioli, A. Pancrazzi, A. Bosi, G. Barosi y A. M. Vannucchi. "Frequency and clinical correlates of JAK2 46/1 (GGCC) haplotype in primary myelofibrosis". Leukemia 24, n.º 8 (3 de junio de 2010): 1533–37. http://dx.doi.org/10.1038/leu.2010.126.

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Vannucchi, Alessandro M. y Paola Guglielmelli. "The JAK2 46/1 (GGCC ) MPN-predisposing haplotype: A risky haplotype, after all". American Journal of Hematology 94, n.º 3 (18 de diciembre de 2018): 283–85. http://dx.doi.org/10.1002/ajh.25367.

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Abdel-Wahab, Omar, Taghi Manshouri, Jay Patel, Kelly Harris, Jin Juan Yao, Cyrus V. Hedvat, Adriana Heguy et al. "TET2 and ASXL1 Mutations in Leukemic Transformation of Chronic Myeloproliferative Neoplasms." Blood 114, n.º 22 (20 de noviembre de 2009): 2894. http://dx.doi.org/10.1182/blood.v114.22.2894.2894.

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Abstract Abstract 2894 Poster Board II-870 Recent studies have identified TET2 and ASXL1 mutations in myeloid malignancies, suggesting that acquisition of these mutant alleles might precede the acquisition of JAK2 in some myeloproliferative neoplasm (MPN) patients. Moreover, the observation that JAK2 mutations are observed in minority of patients with leukemic transformation of JAK2-mutant MPNs suggests the possibility that JAK2 mutations are dispensable for leukemic transformation. However the role of TET2 and ASXL1 mutations in leukemic transformation has not been evaluated. We therefore investigated the mutational status of JAK2, TET2, and ASXL1 in 63 patients with leukemic transformation from a pre-existing MPN, including 49 unpaired secondary acute myeloid leukemia (sAML) samples and 14 patients for whom paired MPN and sAML samples were available. Mutations of TET2 and ASXL1 were found at a higher frequency in sAML samples transformed from MPNs than reported for sporadic MPNs (9/46 (19.6%) and 7/46 (15.2%), respectively). This was also higher than the mutational frequency of TET2 and ASXL1 in de novo AML (6.4% (3/47) and 4.3% (2/47), respectively) but similar to that of AML transformed from MDS (12.8% (5/39) and 15.4% (6/39)). All possible genetic combinations of JAK2, TET2, and ASXL1 status were observed in sAML patients. Analysis of paired samples reveal that TET2 mutations are far more likely to occur at leukemic transformation of MPN than at MPN diagnosis (p=0.013, Fisher's exact test) whereas ASXL1 mutations were equally likely to occur at MPN or sAML. Although mutations in JAK2 and in TET2 may not be retained at leukemic transformation from MPN, mutations in ASXL1 at MPN diagnosis were consistently retained at leukemic transformation. In addition, individual cases were observed where TET2 and/or ASXL1 mutations were found before acquisition of JAK2 mutations or clinical evidence of MPN, as well as cases where TET2 and ASXL1 mutations were acquired during leukemic transformation of a JAK2V617F-positive clone. These data suggest the mutational order of events in MPN and sAML pathogenesis might vary in different patients, and that TET2 and ASXL1 mutations might contribute in different patients to the development of MPN and/or to leukemic transformation. In addition, the identification of transformed AML cases with no evidence of pre-existing JAK2, TET2, and ASXL1 mutations indicates the existence of other, not yet identified, mutations necessary for leukemic transformation of MPNs. Disclosures: Levine: Novartis: Research Funding; TargeGen: Consultancy. Verstovsek:Incyte: ; Exelixis: ; Cephalon: ; SBIO: ; AstraZeneca: .

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Lamy, Matthias, Paola Palazzo, Pierre Agius, Jean Claude Chomel, Jonathan Ciron, Aline Berthomet, Paul Cantagrel et al. "Should We Screen for Janus Kinase 2 V617F Mutation in Cerebral Venous Thrombosis?" Cerebrovascular Diseases 44, n.º 3-4 (2017): 97–104. http://dx.doi.org/10.1159/000471891.

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Background: The presence of Janus Kinase 2 (JAK2) V617F mutation represents a major diagnostic criterion for detecting myeloproliferative neoplasms (MPN) and even in the absence of overt MPN, JAK2 V617F mutation is associated with splanchnic vein thrombosis. However, the actual prevalence and diagnostic value of the JAK2 V617F mutation in patients with cerebral venous thrombosis (CVT) are not known. The aims of this study were to assess the prevalence of JAK2 V617F mutation in a large group of consecutive CVT patients, to detect clinical, biological, and radiological features associated with the mutation, and to determine the long-term venous thrombosis recurrence rate in CVT patients with JAK2 mutation but without overt MPN in order to recommend the best preventive treatment. Methods: This was a prospective study conducted on consecutive patients with a first-ever radiologically confirmed CVT. JAK2 V617F mutation analysis was assessed in all the study subjects. JAK2 V617F-positive patients were followed up to detect new venous thrombotic events. Results: Of the 125 included subjects, 7 were found to have JAK2 V617F mutation (5.6%; 95% CI 2.3-11.2). Older age (p = 0.039) and higher platelet count (p = 0.004) were independently associated with JAK2 V617F positivity in patients without overt MPN. During a mean follow-up period of 59 (SD 46) months, 2 JAK2 V617F-positive patients presented with 4 new venous thromboembolic events. Conclusions: Screening for the JAK2 V617F mutation in CVT patients seems to be useful even in the absence of overt MPN and/or in the presence of other risk factors for CVT because of its relatively high prevalence and the risk of thrombosis recurrence.

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Nguyen, Huong (Marie) y Jason Gotlib. "Insights into the Molecular Genetics of Myeloproliferative Neoplasms". American Society of Clinical Oncology Educational Book, n.º 32 (junio de 2012): 411–18. http://dx.doi.org/10.14694/edbook_am.2012.32.85.

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Overview: The molecular biology of the BCR-ABL1-negative chronic myeloproliferative neoplasms (MPNs) has witnessed unprecedented advances since the discovery of the acquired JAK2 V617F mutation in 2005. Despite the high prevalence of JAK2 V617F in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), and the common finding of dysregulated JAK-STAT signaling in these disorders, it is now appreciated that MPN pathogenesis can reflect the acquisition of multiple genetic mutations that alter several biologic pathways, including epigenetic control of gene expression. Although certain gene mutations are identified at higher frequencies with disease evolution to the blast phase, MPN initiation and progression are not explained by a single, temporal pattern of clonal changes. A complex interplay between acquired molecular abnormalities and host genetic background, in addition to the type and allelic burden of mutations, contributes to the phenotypic heterogeneity of MPNs. At the population level, an inherited predisposition to developing MPNs is linked to a relatively common JAK2-associated haplotype (referred to as ‘46/1’), but it exhibits a relatively low penetrance. This review details the current state of knowledge of the molecular genetics of the classic MPNs PV, ET, and PMF and discusses the clinical implications of these findings.

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Gugliotta, Luigi, Alessandra Iurlo, Gabriele Gugliotta, Alessia Tieghi, Giorgina Specchia, Gianluca Gaidano, Anna Candoni et al. "Clinical and Biological Features in Patients with Ph-Negative Chronic Myeloproliferative Neoplasm Showing Different Molecular Pattern. Comparative Study in 596 Patients of the Registro Italiano Trombocitemie (RIT)". Blood 126, n.º 23 (3 de diciembre de 2015): 4071. http://dx.doi.org/10.1182/blood.v126.23.4071.4071.

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Abstract Background. In patients with Ph-negative chronic myeloproliferative neoplasm (MPN) the molecular pattern, beside other characteristics at diagnosis, has been related to the disease prognosis. Aim. To compare clinical and biological features at diagnosis and during the follow-up in gender/age-matched MPN patients showing different molecular pattern. Material and methods. The Registro Italiano Trombocitemie (RIT) is a web-based registry that includes thrombocythemic MPN patients diagnosed according to PVSG or WHO criteria, registered after 2005, and then prospectically followed. The JAK2 V617F mutation (JAK2+) was reported in 941 (58.4%) out of 1610 tested patients. On the basis of subsequent tests, performed in part of the JAK2 WT (JAK2-) subjects, 103 patients were JAK2-/CALR+ (CALR+), 14 patients were JAK2-/CALR-/MPL+ (MPL+), and 46 were JAK2-/CALR-/MPL- (3NEG). The 103 CALR+ patients were compared with 309 (103 x 3) JAK2+ patients matched for gender, age, and revised diagnosis (WHO 2008 criteria). A similar comparison was done between 46 3NEG patients and other 138 (46 x 3) JAK2+ matched patients. Results. CALR+ and matched JAK2+ patients had, as expected, the same gender distribution (males 41%), the same median age (51 years), and no significant difference (p 0.42) in the WHO diagnosis distribution. CALR+ patients, as compared with JAK2+ patients, showed at diagnosis: higher median platelet (PLT) count (839 vs 718 x109/L, p<0.001); lower median white blood cell (WBC) count (7.3 vs 8.9 x109/L, p<0.001); lower median hemoglobin (Hb, 14.2 vs 14.8 g/dL in males, p 0.01; 12.9 vs 14.0 g/dL in females, p<0.001); lower median hematocrit (HCT, 42.4 vs 45.0 %, p 0.002 in males; 38.7 vs 42.2 in females, p<0.001); lower rate of low (<5) serum erythropoietin (0 vs 32%, p 0.003); lower rate of prior thrombosis (PrTh, 5/103, 4.9% vs 60/309, 19.4%, p<0.001), observed for both arterial and venous PrTh; lower rate of high/intermediate thrombotic risk (IPSET, 37% vs 55%, p 0.003). CARL+ and JAK2+ patients had the same rate of antiplatelet and cytoreductive treatment (96% vs 96%, and 86% vs 84%, respectively). During the follow-up the incidence of thrombotic and hemorrhagic events was not significantly different (1.3 vs 1.1/100 pt-years, and 1.0 vs 0.6/100 pt-years, respectively). Moreover, no significant difference was observed in the incidence of evolution to overt primary myelofibrosis (PMF, 0.76 vs 0.61/100 pt-years), polycythemia vera (PV, 0 vs 0.24/100 pt-years), and AL/MDS (0.08 vs 0.10/100 pt-years). Finally, the same overall survival was found after 5, 10. 15, and 20 years (99, 97, 94, 93%, respectively). 3NEG patients, as compared with JAK2+ matched patients, showed at diagnosis: lower median WBC count (7.9 vs 10.9 x 109/L, p 0.03); lower Hb and/or HCT level (p 0.006); lower rate of splenomegaly (7% vs 28%, p 0.003); lower rate of symptoms (35% vs 51%, p 0.049). No significant difference was found in: median PLT count (700 vs 720 x 109/L, p 0.61); PrTh (7% vs 16%, p 0.11); prior hemorrhage (4.7% vs 7.5%, p 0.52); high/intermediate thrombotic risk (IPSET, 36 vs 48%, p 0.37). Moreover, no significant difference was observed during the follow-up in: antiplatelet and cytoreductive treatment; thrombosis and hemorrhage rate; PMF, PV, and AL/MDS evolution; overall survival. Conclusion. CALR+ patients, as compared with JAK2+ matched patients, although showed a lower thrombotic risk (lower WBC and HCT levels, lower PrTh rate), received the same antiplatelet and cytoreductive treatment, had the same incidence of adverse events during the follow-up (vascular complications and disease evolution/transformation), and had the same overall survival. 3NEG patients, as compared with JAK2+ matched patients, showed results similar to those observed by comparing CALR+ and JAK2+ matched patients. To better define the role of the precise definition of molecular pattern in Ph-MPN patients, new prospective controlled studies seem necessary. Disclosures De Stefano: Janssen Cilag: Research Funding; Roche: Research Funding; Novartis: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Bruno Farmaceutici: Research Funding; Celgene: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Shire: Speakers Bureau. Passamonti:Novartis: Consultancy, Honoraria, Speakers Bureau.

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Bumm, Thomas G. P., Collin Elsea, Lisa G. Wood, Daniel W. Sherbenou, Ian J. Griswold, Marc Loriaux, Brian J. Druker y Michael W. Deininger. "JAK2 V617F Mutation Induces a Myeloproliferative Disorder in Mice." Blood 106, n.º 11 (16 de noviembre de 2005): 376. http://dx.doi.org/10.1182/blood.v106.11.376.376.

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Abstract Background: An activating mutation (V617F) in the JH2 domain of the Jak2 kinase is found in 74%–97% of patients with polycythemia vera (PV), 23%–57% of patients with essential thrombocythemia and 35%–57% of patients with idiopathic myelofibrosis. We studied the effects of this mutant in murine hematopoietic cells in vitro and in vivo. Materials and Methods: Murine wild type (Jak2-WT) and V617F mutant JAK2 (Jak2-V617F) were cloned into the MIGR1-IRES-GFP retroviral vector. BaF3 cells stably expressing mutant and wild type Jak2 were generated by electroporation followed by prolonged culture in IL-3 containing media and FACS selection for GFP-positive cells. Proliferation and viability assays were performed in graded concentrations of IL-3. Bone marrow from 5-FU treated Balb/c mice were infected with JAK2-V617F, JAK2-WT and empty vector retrovirus and injected into lethally irradiated recipients. The mice were monitored by observation and blood counts. Plasma levels of erythropoietin (EPO) were determined by ELISA on day 44 after transplantation. 1-way analysis of variance (ANOVA) was used to compare differences between cell line and hematologic parameters. The relationship between EPO levels and Hct/Hgb was analysed by Pearson correlation. Results: BaF3 cells expressing JAK2-V617F showed enhanced proliferation in response to murine IL-3 compared to cells expressing Jak2-WT (p<0.001) and parental cells (p= 0.009). Similarly, there was a trend for increased viability (p=0.071 vs. Jak-WT and p=0.059 vs. parental cells). Sudden complete IL-3 withdrawal induced >95% cell death, followed by outgrowth of IL-3-independent lines after 20 days. Mice transplanted with Jak2-V617F showed increased median hematocrit (Hct), hemoglobin (Hgb) and median corpuscular volume (MCV) compared to Jak2-WT and empty vector mice (table). There was a trend for increased white cell counts (WBC). Median EPO levels were 65 pg/ml in the Jak2-V617F mice compared to 88 pg/ml in the Jak2-WT and 131 pg/ml in the empty vector controls (p= 0.032). There was a significant correlation between EPO and Hct (p = 0.011, r = −0.677) and Hgb (p= 0.002, r= −0.770) across the three groups of mice. On day 44 post transplant one Jak2-V617F mouse developed trilineage MPD with a Hct of 56.8%, leukocytosis (22.6 x 103/ul) and thrombocytosis (1004 x 103/ul). The peripheral blood smear showed neutrophilia, elevated platelets and multiple nucleated red cells. Necropsy revealed hepatosplenomegaly. Conclusions: (i) JAK2-V617F induces hypersensitivity to IL-3 in BaF3 cells. Complete IL-3 independence was seen only after “crisis” and prolonged culture, suggesting additional mutations may be required. (ii) In a murine transduction-transplantation model JAK2-V617F induces MPD closely mimicking PV. Studies are in progress to determine whether additional phenotypes may be observed in a larger cohort of animals. JAK2-V617F (n= 4) JAK2- WT (n= 4) MIGR-1 vector-control (n= 5) P value (V617F vs. WT) P value (V617F vs. empty vector) Median blood parameters (range) in groups of mice 44 days after transplant Hct (%) 51.1 (44.6–56.8) 43.7 (42.8–45) 43.6 (40.4–45.2) P = 0.015 P= 0.011 Hgb (g/dl) 16.2 (14.6–17.6) 14.6 (14.2–15.4) 14.2 (13–15) P= 0.033 P= 0.010 MCV (fl) 49.5 (47–54) 46.2 (46–47) 46.2 (45–48) P= 0.041 P= 0.031 WBC (103/ul) 9.6 (3.8–22.6) 5.5 (3.6–9.4) 3.4 (2.2–4.6) ns P= 0.096 EPO (pg/ml) 65 (44–98) 88 (80–112) 131 (95–231) ns P= 0.032

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47

Patnaik, M. M., T. L. Lasho, C. M. Finke, N. Gangat, D. Caramazza, S. Siragusa, C. A. Hanson, A. Pardanani y A. Tefferi. "MPL mutation effect on JAK2 46/1 haplotype frequency in JAK2V617F-negative myeloproliferative neoplasms". Leukemia 24, n.º 4 (28 de enero de 2010): 859–60. http://dx.doi.org/10.1038/leu.2010.1.

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48

Quadri, Manuel, Claudia Saitta, Sonia Palamini, Chiara Palmi, Andrea Biondi, Giovanni Cazzaniga y Grazia Fazio. "Targeting JAK2 Gene Rearrangements with a Novel Kinase Inhibitor in a Preclinical Model of Pediatric Acute Lymphoblastic Leukemia". Blood 138, Supplement 1 (5 de noviembre de 2021): 1180. http://dx.doi.org/10.1182/blood-2021-152270.

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Abstract Background. Although the Event Free Survival for Childhood Acute lymphoblastic leukemia (ALL) reaches 85%, the remaining 15% of patients relapse, and 25-40% of them die. Novel molecular targets may increase the efficacy of therapy and reduce treatment toxicity. Among B-other ALL patients, JAK/STAT pathway alterations represent about 7% of the 'Philadelphia-like' cases. JAK2 gene encodes for a non-receptor tyrosine kinase fundamental for hematopoiesis, cellular proliferation and survival. In last years, JAK2 mutations have been widely studied in leukemia and lymphoma, whereas JAK2 fusion genes are still poorly characterized. Aim. This study aims to identify JAK2 fusion genes among BCP-ALL pediatric patients and develop a target strategy in in vitro and in vivo preclinical models. Methods. A targeted capture RNA Next Generation Sequencing strategy was applied to discover JAK2 fusion genes in a large cohort of PCR-based MRD high risk (HR) BCP-ALL pediatric patients. Fusions were validated by RT-PCR and/or FISH. Primary patients' cells have been in vivo expanded in NSG mice. We performed ex vivo and in vivo drug treatments with JAK2 inhibitors; phosphoflow and apoptosis-viability assays were performed in patients' blasts in co-culture with human bone marrow stroma. Results. We identified 10 pediatric cases carrying a JAK2 fusion gene with different partners in single cases, such as ATF7IP, ZEB2, MPRIP, BCR, TLE4, GIT2 and RAB7, in addition to PAX5, which was the only recurrent in three cases. Cells were available from 3 cases, carrying PAX5-JAK2, ATF7IP-JAK2 and ZEB2-JAK2, respectively. After in vivo expansion, we demonstrated that the JAK2 signaling pathway was active at basal level, through phosphorylation on Y1007-1008 JAK2 residues inside the catalytic activation loop, compared to cases wild type for JAK2 and CRLF2 (+70%, two-tailed P value 0.0355); a positive trend was also shown compared to primary cells with P2RY8-CRLF2 rearrangements and JAK2 mutation, as positive controls (+40% two-tailed P value 0.158). The JAK2 downstream effectors pS727-STAT3 and pY694-STAT5 were also activated. We thus setup a JAK2 targeted drug treatment using CHZ868, a new class-II tyrosine kinase inhibitor (TKI) (Novartis, Basel, CH). After 30 minutes of treatment, we appreciated a mean inhibition of -62% of Y1007-1008 JAK2 residues in PAX5-JAK2, -22% in ATF7IP-JAK2 and -35% in ZEB2- JAK2. Contemporarily, we observed a decrease of pS727-STAT3 (-35-50%) and pY694-STAT5 (-15-50%). After 48h monotherapy treatment by CHZ868, we detected apoptosis induction and cell viability decrease between 20- 75% at IC50. In combination with dexamethasone, we assessed a further decrease of viability between 10 to 95%. A biological variability among the three different patients was appreciated, according to the different partner genes. Exclusively for the PAX5-JAK2 fusion, we also performed treatments with the kinase inhibitor BIBF1120/Nintedanib, targeting LCK, which is activated downstream PAX5 fusions and we observed a 20% reduction of cell viability. Importantly, combination of BIBF1120 and CHZ868 showed a synergistic effect (-45%, at IC50). Moreover, we found that ruxolitinib caused autophagy as observed by higher levels of LC3-II compared to untreated cells (+ 45%, p<0.01), with consequent reduction of apoptosis induction. Indeed, active caspase 3 increased when ruxolitinib was given in combination with chloroquine, an autophagy inhibitor (+20% vs ruxolitinib alone, p<0.01). CHZ868 alone or in combination with chloroquine instead does not induce autophagy as LC3-II and active caspase 3 levels are the same of untreated cells. Finally, we demonstrated the in vivo efficacy of CHZ868 in patient derived xenograft model in presence of PAX5-JAK2 fusion. After two weeks of 30mg/Kg daily treatment of CHZ868, we observed a significant reduction of leukemic CD10+/CD19+ cells both in bone marrow (p<0.01, -43%), spleen (p<0.001, -72%), central nervous system (-40%) and peripheral blood (p<0.05, -46%), compared to vehicle mice. Further in vivo experiments are ongoing in other JAK2 fusion settings. Conclusion. CHZ868 is a promising candidate for treatment of BCP-ALL carrying JAK2 fusions, showing high efficacy and specificity, both ex vivo and in vivo. Further studies will include combination with standard chemotherapy drugs with the aim to maintain its efficacy by reducing the intensity and toxicity of chemotherapy. Disclosures Biondi: Novartis: Honoraria; Bluebird: Other: Advisory Board; Incyte: Consultancy, Other: Advisory Board; Colmmune: Honoraria; Amgen: Honoraria.

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Spolverini, Ambra, Amy V. Jones, Andreas Hochhaus, Lisa Pieri, Nicholas C. P. Cross y Alessandro M. Vannucchi. "The myeloproliferative neoplasm-associated JAK2 46/1 haplotype is not overrepresented in chronic myelogenous leukemia". Annals of Hematology 90, n.º 3 (16 de junio de 2010): 365–66. http://dx.doi.org/10.1007/s00277-010-1009-y.

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Trifa, Adrian P., Sorin Crişan, Radu A. Popp, Andrei Cucuianu y Anca D. Buzoianu. "JAK2 46/1 haplotype seems not to be associated with lower limb deep venous thrombosis". Blood Cells, Molecules, and Diseases 45, n.º 3 (octubre de 2010): 199–200. http://dx.doi.org/10.1016/j.bcmd.2010.07.004.

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