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Jones, Amy V., Peter J. Campbell, Philip A. Beer, Susanne Schnittger, Alessandro M. Vannucchi, Katerina Zoi, Melanie J. Percy, et al. "The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms." Blood 115, no. 22 (June 3, 2010): 4517–23. http://dx.doi.org/10.1182/blood-2009-08-236448.
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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 (November 5, 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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Cross, Nicholas C. P., Amy V. Jones, Richard T. Silver, David Oscier, Georgia Metzgeroth, Y. Lynn Wang, Andrew Collins, Andreas Reiter, Francis Grand, and Andrew Chase. "Development of V617F JAK2 Associated Myeloproliferative Neoplasms Is a Non-Random Event That Is Strongly Dependent on JAK2 Haplotype." Blood 112, no. 11 (November 16, 2008): 173. http://dx.doi.org/10.1182/blood.v112.11.173.173.
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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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Cross, Nicholas C. P., Peter Campbell, Philip A. Beer, Susanne Schnittger, Alessandro M. Vannucchi, Katerina Zoi, Melanie Percy, et al. "The JAK2 46/1 Haplotype Predisposes to Myeloproliferative Neoplasms Characterized by Diverse Mutations." Blood 114, no. 22 (November 20, 2009): 433. http://dx.doi.org/10.1182/blood.v114.22.433.433.
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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, and Sylvie Hermouet. "Homologous Recombination of Wild TYPE JAK2, A NOVEL EARLY STEP In the DEVELOPMENT of Myeloproliferative Neoplasm." Blood 118, no. 21 (November 18, 2011): 2805. http://dx.doi.org/10.1182/blood.v118.21.2805.2805.
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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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Olkhovskiy, I. А., M. A. Stolyar, Yu Yu Komarovskiy, A. S. Gorbenko, V. I. Korchagin, E. A. Dunaeva, K. O. Mironov, et al. "Study of the Janus kinase 2 (JAK2) gene haplotype 46/1 association with driver mutations of chronic Ph-negative myeloproliferative neoplasms." Russian journal of hematology and transfusiology 67, no. 3 (October 22, 2022): 377–87. http://dx.doi.org/10.35754/0234-5730-2022-67-3-377-387.
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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, no. 21 (November 19, 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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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, no. 15 (April 14, 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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Kouroupi, Eirini, Jean-Jacques Kiladjian, Christine Chomienne, Christine Dosquet, Sylvia Bellucci, Dominique Valla, and Bruno Cassinat. "The JAK2 46/1 haplotype in splanchnic vein thrombosis." Blood 117, no. 21 (May 26, 2011): 5777–78. http://dx.doi.org/10.1182/blood-2011-03-343657.
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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 (November 29, 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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Hasan, Salma, Jean Pierre Le Couedic, Fabrizia Favale, Barbara Monte-Mor, Catherine Lacout, Nicole Casadevall, Eric Solary, Jean-Luc Villeval, Isabelle Plo, and William Vainchenker. "46/1 Haplotype Permits to Follow JAK2 Homologous Recombination: Modeling JAK2V617F clonal Architecture in PV Patients." Blood 120, no. 21 (November 16, 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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Vannucchi, Alessandro M., and Paola Guglielmelli. "The JAK2 46/1 (GGCC ) MPN-predisposing haplotype: A risky haplotype, after all." American Journal of Hematology 94, no. 3 (December 18, 2018): 283–85. http://dx.doi.org/10.1002/ajh.25367.
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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, no. 22 (November 20, 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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Panovska, Irina, Nadica Matevska, Martin Ivanovski, Sanja Trajkova, Dusko Dukovski, Lidija Cevreska, and Aleksandar Dimovski. "Frequency and Clinical Correlates of JAK2 46/1 Haplotype in Comparison with JAK2V617F Variant in Myeloproliferative Neoplasms: Single Center Experience." Blood 118, no. 21 (November 18, 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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Kouroupi, Eirini G., Bruno Cassinat, Aurelie Plessier, Sylvia Bellucci, Christine Chomienne, Bernard Granchamp, Dominique Valla, and 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, no. 21 (November 19, 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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Angona, Anna, Beatriz Bellosillo, Alberto Alvarez-Larrán, Luz Maria Martinez-Aviles, Laura Camacho, Silvia Pairet, Concepción Fernández, and Carles Besses. "Genetic Predisposition to Molecular Response in Patients with Myeloproliferative Neoplasms Treated with Hydroxycarbamide." Blood 120, no. 21 (November 16, 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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Pacilli, Annalisa, Paola Guglielmelli, Tiziana Fanelli, Alessandro Pancrazzi, Lisa Pieri, Rajmonda Fjerza, and Alessandro M. Vannucchi. "JAK2V617F Clonal Architecture in MPNs during JAK2 Inhibitor Treatment." Blood 126, no. 23 (December 3, 2015): 1630. http://dx.doi.org/10.1182/blood.v126.23.1630.1630.
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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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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, no. 5 (May 11, 2015): 654–60. http://dx.doi.org/10.1111/ijlh.12380.
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Tanaka, Mayumi, Toshiaki Yujiri, Shunsuke Ito, Naoko Okayama, Toru Takahashi, Kenji Shinohara, Yoichi Azuno, Ryouhei Nawata, Yuji Hinoda, and Yukio Tanizawa. "JAK2 46/1 haplotype is associated with JAK2 V617F-positive myeloproliferative neoplasms in Japanese patients." International Journal of Hematology 97, no. 3 (February 22, 2013): 409–13. http://dx.doi.org/10.1007/s12185-013-1295-y.
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Paes, Jhemerson, George A. V. Silva, Andréa M. Tarragô, and Lucivana P. de Souza Mourão. "The Contribution of JAK2 46/1 Haplotype in the Predisposition to Myeloproliferative Neoplasms." International Journal of Molecular Sciences 23, no. 20 (October 20, 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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Mahmood, Shameem, Louise Mellish, Nicholas Lea, Austin G. Kulasekararaj, Atiyeh Abdallah, Sivatharsny Srirangan, and 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, no. 21 (November 19, 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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Zagaria, Antonella, Francesco Tarantini, Luisa Anelli, Paola Orsini, Angela Minervini, Nicoletta Coccaro, Elisa Parciante, et al. "JAK2 Negative Erythrocytosis Associated with JAK2 GGCC_46/1 Haplotype, Calr rs1049481_G, and Normal Erythropoietin Level: Is This a New Entity?" Blood 136, Supplement 1 (November 5, 2020): 28. http://dx.doi.org/10.1182/blood-2020-139450.
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Introduction. The JAK2 haplotype known as "GGCC or 46/1 haplotype" consists of a germline combination of single nucleotide polymorphisms (SNPs) that are inherited together and are frequently associated with the onset of myeloproliferative neoplasms (MPNs) positive for both JAK2 V617 and exon 12 mutations. It has been reported a significant association between JAK2 negative erythrocytosis and the simultaneous occurrence of JAK2 haplotype GGCC_46/1 and CALR rs1049481_G allele, mapping in the 3' UTR of the gene. In the present study, we investigated the presence of JAK2 haplotype GGCC_46/1 and CALR rs1049481_G allele in a more extensive series of erythrocytosis patients and evaluated a possible correlation with serum erythropoietin (EPO) level. Methods. Fifty-nine erythrocytosis patients, diagnosed at our Center from 2009 to 2020, negative for canonical JAK2 mutations, and secondary causes, were included in this study. Forty-nine (83%) out of 59 cases met only two major WHO 2016 diagnostic criteria for polycythemia vera (PV); the remaining 10 cases were "JAK2 negative PV", as they also showed the minor criterion with subnormal serum EPO. Genomic DNA from all patients was extracted from peripheral blood granulocytes and analyzed for the presence of both SNPs. The occurrence of the JAK2 haplotype was investigated by analyzing rs10974944 tagging SNP, using distal JAK2 intron 12 primers (forward: 5'-CTGTGCAGTCCAAACCCATG-3' and reverse: 5'-TTCTCTGCTTGCTAGTGGGT-3'). This amplification generated a PCR product of 272 bp, revealing a C/G substitution by Sanger sequencing. PCR investigated the occurrence of the G/T allele in the SNP rs1049481 in the CALR gene with primers CALR-UTR-F 5'-GACAAGGAGGATGATGAGGACAAA-3' and CALR-UTR-R 5'- AAAAATGAAAGTTCTCGAGTCTCACAGA-3' generating a 205 bp product. In silico data from 2504 healthy individuals of the 1000G Project (1000G) were used as a control group. Fisher's exact test was used to compare the differences of both SNPs and the frequency of their alleles between cases and controls, respectively; the c-square test was employed for evaluating the distribution of JAK2 GGCC haplotype in erythrocytosis patients and controls. Results. Thirty-eight (64.4%) and 21 (35.6%) cases resulted in being positive and negative for the JAK2 GGCC haplotype, respectively. The JAK2 GGCC haplotype occurred to be associated with erythrocytosis as a statistically significant difference in frequency was detected as respect to 2504 healthy individuals from the 1000G Project (p=0.0013). This finding was also confirmed considering the Genome Aggregation Database (gnomAD v2.1.1, https://gnomad.broadinstitute.org/)(p=0.0024). The association was also demonstrated in terms of allelic frequency (p=0.0131) and genotype distribution (p=0.0030). Regarding CALR rs1049481 SNP, a significant difference in the CALR rs1049481_G allelic rate was confirmed in our cohort compared to 1000G controls (p=0.0360). Overall, the association between JAK2 GGCC haplotype and CALR rs1049481_G was observed in 28/59 (47.5%) erythrocytosis cases compared to healthy individuals (628/2504, 25%), and this difference resulted in being statistically significant (p=0.0002). Based on the EPO level, erythrocytosis patients were divided into two groups: normal (49 cases) or subnormal (10 cases). Interestingly, the simultaneous presence of JAK2 GGCC haplotype and CALR rs1049481_G was statistically significantly associated with the erythrocytosis group showing normal EPO (p=0.0133). Conclusions. This study suggests that the JAK2 GGCC haplotype and the presence of the CALR rs1049481_G allele were significantly associated with erythrocytosis cases, negative for canonical JAK2 mutations. Our findings are in line with recent literature evidence showing that germline predisposition factors such as SNPs and haplotypes may play a crucial role in MPN pathogenesis. Moreover, this study shows that patients showing two major WHO 2016 diagnostic criteria (erythrocytosis and panmyelosis) without JAK2 mutations and with normal EPO levels can benefit from the search for germline polymorphisms combination in JAK2 and CALR driver genes for a better diagnostic classification. Therefore, the presence of these polymorphisms could represent a novel minor criterion for the diagnosis of "JAK2 negative PV". Disclosures No relevant conflicts of interest to declare.
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Campiotti, Leonardo, Lorenzo Elli, Matteo B. Suter, Luigina Guasti, and Francesco Pallotti. "JAK2, 46/1 haplotype and chronic myelogenous leukemia: diagnostic and therapeutic potential." Clinical Chemistry and Laboratory Medicine (CCLM) 58, no. 1 (December 18, 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, no. 10 (September 2, 2010): 1809–13. http://dx.doi.org/10.1038/leu.2010.172.
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Stolyar, M. A., O. A. Klimova, A. S. Gorbenko, E. V. Brenner, S. E. Titov, M. K. Ivanov, and 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, no. 1 (November 14, 2017): e8-e10. http://dx.doi.org/10.1111/ijlh.12765.
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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, no. 1 (December 19, 2013): 208–14. http://dx.doi.org/10.1111/jgh.12379.
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Zerjavic, Katja, Boris Zagradisnik, Lidija Lokar, Marjana G. Krasevac, and Nadja K. Vokac. "The association of the JAK2 46/1 haplotype with non-splanchnic venous thrombosis." Thrombosis Research 132, no. 2 (August 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, and F. Ferrer-Marin. "The JAK2 46/1 haplotype does not predispose to CALR-mutated myeloproliferative neoplasms." Annals of Hematology 94, no. 5 (December 9, 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, and A. M. Vannucchi. "Frequency and clinical correlates of JAK2 46/1 (GGCC) haplotype in primary myelofibrosis." Leukemia 24, no. 8 (June 3, 2010): 1533–37. http://dx.doi.org/10.1038/leu.2010.126.
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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, no. 21 (November 15, 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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Patnaik, M. M., T. L. Lasho, C. M. Finke, N. Gangat, D. Caramazza, S. Siragusa, C. A. Hanson, A. Pardanani, and A. Tefferi. "MPL mutation effect on JAK2 46/1 haplotype frequency in JAK2V617F-negative myeloproliferative neoplasms." Leukemia 24, no. 4 (January 28, 2010): 859–60. http://dx.doi.org/10.1038/leu.2010.1.
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Trifa, Adrian P., Andrei Cucuianu, Ljubomir Petrov, Laura Urian, Mariela S. Militaru, Delia Dima, Ioan V. Pop, and 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, no. 10 (April 27, 2010): 979–83. http://dx.doi.org/10.1007/s00277-010-0960-y.
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Spolverini, Ambra, Amy V. Jones, Andreas Hochhaus, Lisa Pieri, Nicholas C. P. Cross, and Alessandro M. Vannucchi. "The myeloproliferative neoplasm-associated JAK2 46/1 haplotype is not overrepresented in chronic myelogenous leukemia." Annals of Hematology 90, no. 3 (June 16, 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, and Anca D. Buzoianu. "JAK2 46/1 haplotype seems not to be associated with lower limb deep venous thrombosis." Blood Cells, Molecules, and Diseases 45, no. 3 (October 2010): 199–200. http://dx.doi.org/10.1016/j.bcmd.2010.07.004.
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Wang, J., Z. Xu, L. Liu, R. P. Gale, N. C. P. Cross, A. V. Jones, T. Qin, et al. "JAK2V617F allele burden, JAK2 46/1 haplotype and clinical features of Chinese with myeloproliferative neoplasms." Leukemia 27, no. 8 (January 22, 2013): 1763–67. http://dx.doi.org/10.1038/leu.2013.21.
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Zhang, Xinju, Tingting Hu, Zhiyuan Wu, Zhihua Kang, Weiwei Liu, and Ming Guan. "The JAK2 46/1 haplotype is a risk factor for myeloproliferative neoplasms in Chinese patients." International Journal of Hematology 96, no. 5 (September 29, 2012): 611–16. http://dx.doi.org/10.1007/s12185-012-1169-8.
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Cleyrat, Cédric, Jaroslav Jelinek, François Girodon, Marjorie Boissinot, Thierry Ponge, Jean-Luc Harousseau, Jean-Pierre Issa, Sylvie Hermouet, and Sylvie Hermouet. "Polycythemia Vera with Multiple Clones Carrying Different Mutations (L611V, V617F, L611V/V617F) in Exon 14 of JAK2." Blood 114, no. 22 (November 20, 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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Villani, Laura, Gaetano Bergamaschi, Massimo Primignani, Vittorio Rosti, Adriana Carolei, Valentina Poletto, Paolo Catarsi, Ambra Spolverini, Alessandro M. Vannucchi, and Giovanni Barosi. "JAK2 46/1 haplotype predisposes to splanchnic vein thrombosis-associated BCR-ABL negative classic myeloproliferative neoplasms." Leukemia Research 36, no. 1 (January 2012): e7-e9. http://dx.doi.org/10.1016/j.leukres.2011.08.008.
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Tefferi, Ayalew, Terra L. Lasho, Mythri Mudireddy, Christy M. Finke, Curtis A. Hanson, Rhett P. Ketterling, Naseema Gangat, and Animesh Pardanani. "The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly-annotated patients with primary myelofibrosis." American Journal of Hematology 94, no. 3 (December 5, 2018): 299–305. http://dx.doi.org/10.1002/ajh.25349.
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Pagliarini e Silva, S., BC Santos, EM Pereira, ME Ferreira, EC Baraldi, AM Sell, and JE Visentainer. "Evaluation of the association between the JAK2 46/1 haplotype and chronic myeloproliferative neoplasms in a Brazilian population." Clinics 68, no. 1 (January 28, 2013): 5–9. http://dx.doi.org/10.6061/clinics/2013(01)oa02.
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Bendaly, Edmond A., Saud S. Rahman, Samiah Zafar, Karen Haglof, Sherif Ibrahim, and Bruce G. Raphael. "Is JAK2 Inducible by Cytotoxic Chemotherapy?" Blood 114, no. 22 (November 20, 2009): 4979. http://dx.doi.org/10.1182/blood.v114.22.4979.4979.
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Abstract Abstract 4979 Introduction The JAK2V617F mutation accounts for most cases of myeloproliferative neoplasms (MPN). Only a few case reports of MPN following cytotoxic chemotherapy have been reported, and all of them were published prior to the discovery of the JAK2V617F mutation. We report a series of 6 patients who developed a JAK2V617F positive MPN following cytotoxic chemotherapy. Patients From 2006 to 2009, 6 patients with a history of a hematologic or an oncologic malignancy who developed an MPN were identified and their medical records retrospectively reviewed. One patient had acute lymphoblastic leukemia, 1 had Hodgkin lymphoma, 1 had squamous cell carcinoma of the head and neck, 1 had cervical cancer, and 2 had breast cancer. All patients were in remission from their primary malignancies at the time the MPN was diagnosed. Five were females. The median age at diagnosis was 72 years. Median time to development of the myeloproliferative neoplasm was 14 years. Type of chemotherapy exposure, MPN diagnosis and time to MPN in each case is shown in the table below. The JAK2V617F mutation was detected either in the peripheral blood or the bone marrow of all patients. There was no predominance of any specific MPN diagnosis. Patients who received platinum-based chemotherapy developed the MPN sooner than those who received alkylators (6 vs 17.5 years respectively). Treatment consisted of phlebotomy, hydroxyurea, anagrelide, aspirin or a combination as deemed appropriate by the treating hematologist. Conclusion These findings lead us to hypothesize whether the development of JAK2V617F positive MPN may be related to prior exposure to cytotoxic chemotherapy. Exposure to platinum-based chemotherapy may cause the disorder to appear sooner compared with exposure to alkylators. Recently, JAK2V617F positive MPN was found to be strongly associated with a specific constitutional haplotype, 46/11 suggesting increased susceptibility to this mutation. Chromosomal analyses are planned to show whether any of the reported patients exhibit this haplotype. Ref: 1.Jones et al, Nat Genet. 2009 Apr;41(4):446-9. 2009 Mar 15. The authors have no relevant disclosure. Disclosures No relevant conflicts of interest to declare.
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Alvarez-Larrán, Alberto, Anna Angona, Luz Martínez-Avilés, Beatriz Bellosillo, and Carlos Besses. "Influence of JAK2 46/1 haplotype in the natural evolution of JAK2V617F allele burden in patients with myeloproliferative neoplasms." Leukemia Research 36, no. 3 (March 2012): 324–26. http://dx.doi.org/10.1016/j.leukres.2011.09.029.
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Nguyen, Huong (Marie), and Jason Gotlib. "Insights into the Molecular Genetics of Myeloproliferative Neoplasms." American Society of Clinical Oncology Educational Book, no. 32 (June 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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Li, Sheng-li, Pei-jin Zhang, Gui-xiang Sun, and Zhao-jun Lu. "The JAK2 46/1 haplotype (GGCC) in myeloproliferative neoplasms and splanchnic vein thrombosis: a pooled analysis of 26 observational studies." Annals of Hematology 93, no. 11 (July 13, 2014): 1845–52. http://dx.doi.org/10.1007/s00277-014-2134-9.
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Tefferi, A., T. L. Lasho, M. M. Patnaik, C. M. Finke, K. Hussein, W. J. Hogan, M. A. Elliott, M. R. Litzow, C. A. Hanson, and A. Pardanani. "JAK2 germline genetic variation affects disease susceptibility in primary myelofibrosis regardless of V617F mutational status: nullizygosity for the JAK2 46/1 haplotype is associated with inferior survival." Leukemia 24, no. 1 (October 22, 2009): 105–9. http://dx.doi.org/10.1038/leu.2009.225.
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Irvin-Barnwell, Elizabeth A., Ajay Yesupriya, Miyono Hendrix, Vince Seaman, Sean Mochal, Stanimila Nikolova, Ronald Hoffman, Steve Dearwent, and Suzanne Cordovado. "Prevalence Of The JAK2V617F Mutation and Associated Risk Haplotype and Determination Of Demographic and Lifestyle Risk Factors In The US Population, Nhanes 1999-2002." Blood 122, no. 21 (November 15, 2013): 391. http://dx.doi.org/10.1182/blood.v122.21.391.391.
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Abstract Background In 2008, the WHO released new diagnostic criteria for polycythemia vera (PV), which included testing for the JAK2V617F mutation. The JAK2V617F mutation is associated with PV and other myeloproliferative neoplasms (MPN) and is present in approximately 97% of all PV cases. A germ-line haplotype, referred to as 46/1, has been reported to be associated with acquisition of JAK2V617F. The exact hierarchical position of JAK2V617F and the risk haplotype in the pathogenesis and phenotypic variability of the MPNs remains unclear. Since the current literature on the prevalence of the JAK2V617F mutation in non-MPN populations is limited, the objective of our study was to determine the JAK2V617F prevalence and the 46/1 risk haplotype in the general, non-institutionalized US population. We evaluated demographic information, lifestyle factors, and body burden levels of environmental contaminants to determine if they correlated with JAK2-status. Methods The NHANES surveys are conducted by the National Center for Health Statistics (NCHS) at the Centers for Disease Control and Prevention (CDC). In order to obtain a representative sample of the civilian non-institutionalized US population, the surveys consisted of a complex multistage sampling design including questionnaire and examination components, as well as the use of blood specimens for a wide variety of analytical purposes. Consent for use of blood specimens for genetic research purposes is permitted in participants aged 20 years and greater. DNA was collected from 7,839 participants (NHANES, 1999-2002). To detect JAK2V617F, real-time quantitative polymerase chain reaction (qPCR) was used for screening. All JAK2V617F(+) samples were confirmed by an independent laboratory. Two tagged single-nucleotide polymorphism (SNPs), rs12340895 and rs12343867, were genotyped using allelic discrimination. The risk haplotype was empirically determined in JAK2V617F(+) specimens using mutation specific amplification followed by single allele sequence based typing. The mutation and risk haplotype prevalence was determined and frequencies calculated using race/ethnicity, age, and sex as variables. Results The JAK2V617F mutation prevalence was 0.62% in the US general population. Age was the only demographic factor that was significantly associated with the JAK2V617F mutation (p-value = 0.0015). Of the 65 participants who tested positive for JAK2V617F, 10% were between the ages 20-39, 32% were 40-59, and 58% were 60 years and older. Diagnosis of a blood cancer, leukemia, or other related cancer was not reported in any of the JAK2V617F(+) participants. However, PV and other MPNs were not designated as reportable cancers until 2001, and the questionnaire was administered in 1999-2002. After adjusting for race/ethnicity and age, exposure to environmental contaminants was not found to be associated with the JAK2V617F mutation. The haplotype tagging SNP analysis showed a significant association with JAK2V617F(+) participants versus the JAK2V617F (-) participants. However, when the haplotype was empirically determined with single allele sequencing of the informative heterozygous JAK2V617F(+) participants (N=40), the mutation was detected on the 46/1 haplotype in only 55% of the JAK2V617F(+) chromosomes, which was lower than previously reported in MPN populations. The JAK2V617F mutation was also detected on the common non-risk haplotype (T-C) in 25% of the chromosomes and on less common haplotypes (C-C, T-G) in 21% of the chromosomes. Conclusions This is the only study to examine the prevalence of JAK2V617F in the US general population. When analyzing a large population-based data set, the analysis showed that the JAK2V617F mutation is present in persons who did not report having an MPN. The incidence of the JAK2V617F was directly correlated with age, and was consistent with the known age of onset of MPNs. Whether this group of individuals has a pre-clinical form of an MPN or the detection of JAKV617F is a transient phenomenon remains unknown. The frequency of the two haplotype-tagging SNPs in the normal population was similar to that previously reported. The risk haplotype however, was not more commonly seen associated with JAK2V617F, indicating that the JAK2V617F may not arise preferentially on the 46/1 risk haplotype. These studies provide important epidemiological information about the occurrence of JAK2V617F in “normal” individuals. Disclosures: No relevant conflicts of interest to declare.
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Wang, Linghua, Sabina Swierczek, Kimberly Hickman, Soo-Jin Kim, David A. Wheeler, and Josef Prchal. "Molecular Characterization Of Polycythemia Vera Based On The Relationship Of JAK2V617F and 9pUPD." Blood 122, no. 21 (November 15, 2013): 1607. http://dx.doi.org/10.1182/blood.v122.21.1607.1607.
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Abstract The gain-of-function mutation at codon 617 of JAK2 (JAK2V617F) is the most common somatic event observed in patients with polycythemia vera (PV), occurring in over 95% of PV patients. JAK2V617F confers cytokine hypersensitivity and cytokine-independent growth of erythroid progenitors, which are characteristic features of PV. Homozygous JAK2V617F is observed in about half of PV patients, whereas it is rarely seen in essential thrombocythemia (2-4%) and other myeloproliferative neoplasms. Homozygous JAK2V617F has been assumed to result from homozygous recombination, leading to uniparental disomy on 9p (9pUPD). It has been reported that the JAK2 46/1 (GGCC) haplotype may predispose carriers to the JAK2V617F mutation, and the JAK2V617F mutation facilities the acquisition of homozygous JAK2V617F. Challenging this view is a single study reporting 9pUPD in two PV subjects with wild-type JAK2, suggesting that in these two individuals, 9pUPD might have preceded the JAK2V617F mutation (Blood. 2011;118(24):6468-6470). However, the relationship between JAK2V617F and 9pUPD, the frequency of this new PV molecular subtype, its clinical relevance, and the stability of this genotype need to be systematically defined in a larger sample cohort. To address this, we combined whole-exome sequencing (WXS) of DNA from 31 consecutive PV patients with high-resolution SNP arrays, and further validated our findings in two additional cohorts comprising 59 PV consecutive patients collected from a single institution. In addition, we investigated the stability of each molecular subtype by using serial samples collected from 25 PV patients. We obtained an average of 125x coverage on JAK2 locus by WXS (Illumina Hiseq2000) and 2225x coverage by targeted deep sequencing using Ion PGM sequencer. Analysis of these data shows that the relationship between the JAK2 locus and 9pUPD is more complex than originally assumed. We defined 4 subgroups: 41% of patients had JAK2V617F in a heterozygous state without detectable 9pUPD (Subgroup I); 43% of patients had JAK2V617F with an allelic fraction in direct proportion to the level of 9pUPD (Subgroup II; homozygous JAK2V617F); 10% of patients harbored 9pUPD at approximately twice the level of the JAK2V617F allelic burden (Subgroup III; UPD with heterozygous JAK2V617F); and a small subset (6%) of patients exhibited trisomy of 9p, generating 3 copies of the JAK2 allele by chromosome duplication (Subgroup IV). No difference in the frequency of the JAK2 46/1 (GGCC) haplotype was found among these 4 subgroups. We found that this subtype classification was stable over time in over 60% of patients, whereas it transformed among the 9pUPD-positive subtypes in the remaining patients, indicating the outgrowth of a new PV subclone. While 2 PV patients with 9pUPD and wild-type JAK2 were previously reported (Blood. 2011;118(24):6468-6470), we now show a relative high proportion of PV patients having the novel, previously not recognized JAK2 genotype; i.e. JAK2 9pUPD with heterozygous JAK2V617F mutation. Our study will provide novel perspectives on the molecular basis of the evolution of PV and a better understanding of the roles of JAK2V617F and 9pUPD in this disease. Disclosures: No relevant conflicts of interest to declare.
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Martínez-Trillos, Alejandra, Margherita Maffioli, Dolors Colomer, Alberto Alvarez-Larrán, Arturo Pereira, Anna Angona, Beatriz Bellosillo, and Francisco Cervantes. "Relationship between the 46/1 haplotype of the JAK2 gene and the JAK2 mutational status and allele burden, the initial findings, and the survival of patients with myelofibrosis." Annals of Hematology 93, no. 5 (December 15, 2013): 797–802. http://dx.doi.org/10.1007/s00277-013-1989-5.
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Gau, Jyh-Pyng, Chih-Cheng Chen, Yi-Sheng Chou, Chia-Jen Liu, Yuan-Bin Yu, Liang-Tsai Hsiao, Jin-Hwang Liu, et al. "No increase of JAK2 46/1 haplotype frequency in essential thrombocythemia with CALR mutations: Functional effect of the haplotype limited to allele with JAK2V617F mutation but not CALR mutation." Blood Cells, Molecules, and Diseases 55, no. 1 (June 2015): 36–39. http://dx.doi.org/10.1016/j.bcmd.2015.03.009.
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Mead, Adam J., Michelle Rugless, Petter Woll, Ruth Clifford, Debbie Atkinson, Simon Moule, Nicola Bienz, et al. "Germline Activating JAK2 V617I Mutation in a Family with Hereditary Thrombocytosis." Blood 118, no. 21 (November 18, 2011): 1738. http://dx.doi.org/10.1182/blood.v118.21.1738.1738.
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Abstract Abstract 1738 Since the initial description of V617F somatic mutation in patients with Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), a remarkable association between alterations in the JAK2 gene and MPNs has emerged. In addition to V617F, a number of other mutations have been detected in exons 12–15 of the JAK2 gene. Furthermore, a specific JAK2 haplotype predisposes to somatic V617F mutation and MPN. However, the link between JAK mutation and MPNs is not straightforward. For example, in familial cases of MPNs, occurrence of V617F is heterogeneous and occurs as a somatic rather than germline mutation. The underlying inherited genetic abnormality in many of these cases remains unknown. Similarly, occurrence of JAK2 V617F in sporadic MPNs is also heterogeneous and is associated with variable disease characteristics. Thus, understanding of the relationship between JAK2 mutation and MPN disease phenotype remains far from complete. We herein report a family with germline V617I mutation (Figure 1), associated with mild/moderate thrombocythaemia and thrombosis. All patients had normal haematocrit, WBC and peripheral blood (PB) morphology without splenomegaly or other abnormality on physical examination. P1: Presented in 2006 at the age of 53 with a significant ischaemic cerebrovascular event and a platelet count of 750 × 109/l, with a history of longstanding thrombocythaemia (>10 years; 700–970 × 109/l). Bone marrow examination showed normal architecture with increased numbers of morphologically normal megakaryocytes and no fibrosis. She was commenced on aspirin and hydroxycarbamide resulting in good control of the platelet count. Aspirin was not tolerated due to recurrent epistaxis. Subsequent JAK2 mutation screening by pyrosequencing demonstrated an abnormal pyrogram pattern subsequently identified to be V617I by Sanger sequencing. Quantification of allelic level by a pyrosequencing assay designed to detect V617I confirmed heterozygous (≈50%) V617I in PB mononuclear cells (MNCs), CD3+ cells, CD66+ myeloid cells, buccal swab DNA and hair follicle DNA. P2: Daughter of P1. 34 years. Asymptomatic. Persistent thrombocythemia (470–604 × 109/l). Heterozygous (≈50%) V617I in PB MNCs, CD3+ T cells, CD66+ myeloid cells, buccal swab DNA and hair follicle DNA. P3: Son of P1. 36 years. Asymptomatic. Persistent thrombocythemia (606–648 × 109/l). Heterozygous (≈50%) V617I in PB MNCs, CD3+ T cells, CD66+ myeloid cells and buccal swab DNA. P4: Son of P1. 38 years. Asymptomatic. Persistent thrombocythemia (456–526 × 109/l). Heterozygous (≈50%) V617I in PB MNCs, CD3+ T cells, CD66+ myeloid cells and buccal swab DNA. P5: Daughter of P1. 40 years. Platelet count 294 × 109/l. V617I negative in all tissues. V617I has been previously reported to occur rarely in MPN (PMID: 19074595) and to be constitutively-activating in cell line models (PMID: 18326042) and molecular dynamic simulations (PMID: 19744331). Single cell intracellular quantitative pSTAT3 FACS analysis of PB cells from P1-4 demonstrated GCSF hyper-responsiveness of V617I positive PB CD33+ and CD34+ cells. For example, in comparison with normal controls (NC; n=6) V617I CD33+ myeloid cells (n=4) showed a 14-fold increased pSTAT3 mean fluorescent intensity relative to unstimulated cells in response to 15 minutes stimulation with 0.8 ng/ml GCSF (11% vs 156%; P<.001). BFU-E and CFU-MK in PB were not significantly different between NCs (n=4) and V617I (n=4). CFU-GM were increased in the PB of V617I patients (25 vs 46 colonies/200,000 PB MNCs; P<.05). Cytokine independent colonies were not observed. Single nucleotide polymorphism array did not reveal any additional acquired abnormalities in P1-4. None of the patients carried a JAK2 46/1 haplotype. Patients 2–4 are currently under observation and receiving low-dose aspirin only. Germline activating JAK2 mutation is a previously unreported cause of inherited thrombocythaemia (autosomal dominant) and should be considered in familial cases or when rare JAK2 mutations are detected. Importantly, V617F allele specific PCR, would not detect such mutations and, consequently, it is possible that similar cases may have been missed. Finally, the mild/moderate thrombocytosis (without evidence of fibrosis over 50 years) observed with human germline V617I provides fundamental insights into the role of JAK2 mutations in the pathophysiology of human MPNs. Disclosures: No relevant conflicts of interest to declare.