{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:14:29Z","timestamp":1790788469032,"version":"4.1.0"},"reference-count":35,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,2,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Approximately 10% to 15% of patients with essential thrombocythemia (ET) lack the common driver mutations, so-called \u201ctriple-negative\u201d (TN) disease. We undertook a systematic approach to investigate for somatic mutations and delineate gene expression signatures in 46 TN patients and compared the results to those with known driver mutations and healthy volunteers. Deep, error-corrected, next-generation sequencing of peripheral blood mononuclear cells using the HaloPlexHS platform and whole-exome sequencing was performed. Using this platform, 10 (22%) of 46 patients had detectable mutations (MPL, n = 6; JAK2V617F, n = 4) with 3 of 10 cases harboring germline MPL mutations. RNA-sequencing and DNA methylation analysis were also performed by using peripheral blood mononuclear cells. Pathway analysis comparing healthy volunteers and ET patients (regardless of mutational status) identified significant enrichment for genes in the tumor necrosis factor, NF\u03baB, and MAPK pathways and upregulation of platelet proliferative drivers such as ITGA2B and ITGB3. Correlation with DNA methylation showed a consistent pattern of hypomethylation at upregulated gene promoters. Interrogation of these promoter regions highlighted enrichment of transcriptional regulators, which were significantly upregulated in patients with ET regardless of mutation status, including CEBP\u03b2 and NF\u03baB. For \u201ctrue\u201d TN ET, patterns of gene expression and DNA methylation were similar to those in ET patients with known driver mutations. These observations suggest that the resultant ET phenotype may, at least in part and regardless of mutation type, be driven by transcriptional misregulation and may propagate downstream via the MAPK, tumor necrosis factor, and NF\u03baB pathways with resultant JAK-STAT activation. These findings identify potential novel mechanisms of disease initiation that require further evaluation.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020003172","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T20:02:36Z","timestamp":1613851356000},"page":"1059-1068","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":23,"title":["Patients with triple-negative,\n                    <i>JAK2<\/i>\n                    V617F- and\n                    <i>CALR<\/i>\n                    -mutated essential thrombocythemia share a unique gene expression signature"],"prefix":"10.1182","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4784-7324","authenticated-orcid":false,"given":"Samah","family":"Alimam","sequence":"first","affiliation":[{"name":"Department of Haematology, Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, London, United Kingdom;"},{"name":"Department of Medical and Molecular Genetics, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Villiers","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9333-5296","authenticated-orcid":false,"given":"Richard","family":"Dillon","sequence":"additional","affiliation":[{"name":"Department of Haematology, Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, London, United Kingdom;"},{"name":"Department of Medical and Molecular Genetics, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manohursingh","family":"Runglall","sequence":"additional","affiliation":[{"name":"NIHR Comprehensive Biomedical Research Centre at Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust in partnership with King\u2019s College London and King\u2019s College Hospital, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Haematology, King\u2019s College NHS Trust, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0048-4100","authenticated-orcid":false,"given":"Prodromos","family":"Chatzikyriakou","sequence":"additional","affiliation":[{"name":"Genetics and Molecular Medicine Research Division, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Lavender","sequence":"additional","affiliation":[{"name":"School of Immunology & Microbial Sciences, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anju","family":"Kanda","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6362-4481","authenticated-orcid":false,"given":"Ken","family":"Mills","sequence":"additional","affiliation":[{"name":"Centre for Cancer Research and Cell Biology, Queen\u2019s University, Belfast, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5335-2726","authenticated-orcid":false,"given":"Beatriz","family":"Bellosillo Paricio","sequence":"additional","affiliation":[{"name":"Laboratori de Diagn\u00f2stic Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Kaufman-Cook","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Ord","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0347-4207","authenticated-orcid":false,"given":"Shahram","family":"Kordasti","sequence":"additional","affiliation":[{"name":"Department of Haematology, Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, London, United Kingdom;"},{"name":"Systems Cancer Immunology, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepti","family":"Radia","sequence":"additional","affiliation":[{"name":"Department of Haematology, Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Woodley","sequence":"additional","affiliation":[{"name":"Department of Haematology, Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, London, United 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