Christopher Puli'uvea, Tracey Immanuel, Taryn N Green, Peter Tsai, Peter R Shepherd, Maggie L Kalev-Zylinska
{"title":"从独特的新西兰患者队列中洞察 JAK2-I724T 变体在骨髓增生性肿瘤中的作用。","authors":"Christopher Puli'uvea, Tracey Immanuel, Taryn N Green, Peter Tsai, Peter R Shepherd, Maggie L Kalev-Zylinska","doi":"10.1080/16078454.2023.2297597","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to compile bioinformatic and experimental information for <i>JAK2</i> missense variants previously reported in myeloproliferative neoplasms (MPN) and determine if germline <i>JAK2</i>-I724T, recently found to be common in New Zealand Polynesians, associates with MPN.</p><p><strong>Methods: </strong>For all <i>JAK2</i> variants found in the literature, gnomAD_exome allele frequencies were extracted and REVEL scores were calculated using the dbNSFP database. We investigated the prevalence of <i>JAK2</i>-I724T in a cohort of 111 New Zealand MPN patients using a TaqMan assay, examined its allelic co-occurrence with <i>JAK2</i>-V617F using Oxford Nanopore sequencing, and modelled the impact of I724T on JAK2 using I-Mutant and ChimeraX software.</p><p><strong>Results: </strong>Several non-V617F <i>JAK2</i> variants previously reported in MPN had REVEL scores greater than 0.5, suggesting pathogenicity. <i>JAK2</i>-I724T (REVEL score 0.753) was more common in New Zealand Polynesian MPN patients (n = 2/27; 7.4%) than in other New Zealand patients (n = 0/84; 0%) but less common than expected for healthy Polynesians (n = 56/377; 14.9%). Patients carrying I724T (n = 2), one with polycythaemia vera and one with essential thrombocythaemia, had high-risk MPN. Both patients with <i>JAK2</i>-I724T were also positive for <i>JAK2</i>-V617F, found on the same allele as I724T, as well as separately. In silico modelling did not identify noticeable structural changes that would give <i>JAK2</i>-I724T a gain-of-function.</p><p><strong>Conclusion: </strong>Several non-canonical <i>JAK2</i> variants with high REVEL scores have been reported in MPN, highlighting the need to further understand their relationship with disease. The <i>JAK2</i>-I724T variant does not drive MPN, but additional investigations are required to exclude any potential modulatory effect on the MPN phenotype.</p>","PeriodicalId":13161,"journal":{"name":"Hematology","volume":null,"pages":null},"PeriodicalIF":2.0000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Insights into the role of JAK2-I724T variant in myeloproliferative neoplasms from a unique cohort of New Zealand patients.\",\"authors\":\"Christopher Puli'uvea, Tracey Immanuel, Taryn N Green, Peter Tsai, Peter R Shepherd, Maggie L Kalev-Zylinska\",\"doi\":\"10.1080/16078454.2023.2297597\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>This study aimed to compile bioinformatic and experimental information for <i>JAK2</i> missense variants previously reported in myeloproliferative neoplasms (MPN) and determine if germline <i>JAK2</i>-I724T, recently found to be common in New Zealand Polynesians, associates with MPN.</p><p><strong>Methods: </strong>For all <i>JAK2</i> variants found in the literature, gnomAD_exome allele frequencies were extracted and REVEL scores were calculated using the dbNSFP database. We investigated the prevalence of <i>JAK2</i>-I724T in a cohort of 111 New Zealand MPN patients using a TaqMan assay, examined its allelic co-occurrence with <i>JAK2</i>-V617F using Oxford Nanopore sequencing, and modelled the impact of I724T on JAK2 using I-Mutant and ChimeraX software.</p><p><strong>Results: </strong>Several non-V617F <i>JAK2</i> variants previously reported in MPN had REVEL scores greater than 0.5, suggesting pathogenicity. <i>JAK2</i>-I724T (REVEL score 0.753) was more common in New Zealand Polynesian MPN patients (n = 2/27; 7.4%) than in other New Zealand patients (n = 0/84; 0%) but less common than expected for healthy Polynesians (n = 56/377; 14.9%). Patients carrying I724T (n = 2), one with polycythaemia vera and one with essential thrombocythaemia, had high-risk MPN. Both patients with <i>JAK2</i>-I724T were also positive for <i>JAK2</i>-V617F, found on the same allele as I724T, as well as separately. In silico modelling did not identify noticeable structural changes that would give <i>JAK2</i>-I724T a gain-of-function.</p><p><strong>Conclusion: </strong>Several non-canonical <i>JAK2</i> variants with high REVEL scores have been reported in MPN, highlighting the need to further understand their relationship with disease. The <i>JAK2</i>-I724T variant does not drive MPN, but additional investigations are required to exclude any potential modulatory effect on the MPN phenotype.</p>\",\"PeriodicalId\":13161,\"journal\":{\"name\":\"Hematology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Hematology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/16078454.2023.2297597\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/10 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hematology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/16078454.2023.2297597","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/10 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Insights into the role of JAK2-I724T variant in myeloproliferative neoplasms from a unique cohort of New Zealand patients.
Objectives: This study aimed to compile bioinformatic and experimental information for JAK2 missense variants previously reported in myeloproliferative neoplasms (MPN) and determine if germline JAK2-I724T, recently found to be common in New Zealand Polynesians, associates with MPN.
Methods: For all JAK2 variants found in the literature, gnomAD_exome allele frequencies were extracted and REVEL scores were calculated using the dbNSFP database. We investigated the prevalence of JAK2-I724T in a cohort of 111 New Zealand MPN patients using a TaqMan assay, examined its allelic co-occurrence with JAK2-V617F using Oxford Nanopore sequencing, and modelled the impact of I724T on JAK2 using I-Mutant and ChimeraX software.
Results: Several non-V617F JAK2 variants previously reported in MPN had REVEL scores greater than 0.5, suggesting pathogenicity. JAK2-I724T (REVEL score 0.753) was more common in New Zealand Polynesian MPN patients (n = 2/27; 7.4%) than in other New Zealand patients (n = 0/84; 0%) but less common than expected for healthy Polynesians (n = 56/377; 14.9%). Patients carrying I724T (n = 2), one with polycythaemia vera and one with essential thrombocythaemia, had high-risk MPN. Both patients with JAK2-I724T were also positive for JAK2-V617F, found on the same allele as I724T, as well as separately. In silico modelling did not identify noticeable structural changes that would give JAK2-I724T a gain-of-function.
Conclusion: Several non-canonical JAK2 variants with high REVEL scores have been reported in MPN, highlighting the need to further understand their relationship with disease. The JAK2-I724T variant does not drive MPN, but additional investigations are required to exclude any potential modulatory effect on the MPN phenotype.
期刊介绍:
Hematology is an international journal publishing original and review articles in the field of general hematology, including oncology, pathology, biology, clinical research and epidemiology. Of the fixed sections, annotations are accepted on any general or scientific field: technical annotations covering current laboratory practice in general hematology, blood transfusion and clinical trials, and current clinical practice reviews the consensus driven areas of care and management.