{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:05:18Z","timestamp":1790996718224,"version":"4.1.0"},"reference-count":51,"publisher":"American Society of Hematology","issue":"23","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK-cell expansion is challenging. We assessed the value of killer immunoglobulin-like receptor(KIR) phenotyping and targeted high-throughput sequencing in a cohort of 114 consecutive patients with NK cell proliferation, retrospectively assigned to a CLPD-NK group (n = 46) and a reactive NK group (n = 68). We then developed an NK-cell clonality score combining flow cytometry and molecular profiling with a positive predictive value of 93%. STAT3 and TET2 mutations were respectively identified in 27% and 34% of the patients with CLPD-NK, constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK preferentially exhibited a CD16low phenotype, more frequently displayed a lower platelet count, and was associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed whole-exome sequencing of sorted, myeloid, T, and NK cells and found that TET2 mutations were shared by myeloid and NK cells in 3 of 4 cases. Thus, we hypothesized that TET2 alterations occur in early hematopoietic progenitors which could explain a potential link between CLPD-NK and myeloid malignancies. Finally, we analyzed the transcriptome by RNA sequencing of 7 CLPD-NK and evidenced 2 groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including 2 TET2-mutated cases, significantly underexpressed genes known to be downregulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK-cell proliferative disorders and, potentially, new therapeutic opportunities.<\/jats:p>","DOI":"10.1182\/blood.2020006721","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T18:53:37Z","timestamp":1610736817000},"page":"3237-3250","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":63,"title":["Linking the KIR phenotype with\n                    <i>STAT3<\/i>\n                    and\n                    <i>TET2<\/i>\n                    mutations to identify chronic lymphoproliferative disorders of NK cells"],"prefix":"10.1182","volume":"137","author":[{"given":"C\u00e9dric","family":"Pastoret","sequence":"first","affiliation":[{"name":"Laboratoire d\u2019H\u00e9matologie, Centre Hospitalier Universitaire de Rennes, Rennes, France;"},{"name":"INSERM, Unit\u00e9 Mixte de Recherche (UMR) 1236, Etablissement Fran\u00e7ais du sang Bretagne, Universit\u00e9 Rennes 1, Rennes, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Desmots","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019H\u00e9matologie, Centre Hospitalier Universitaire de Rennes, Rennes, France;"},{"name":"INSERM, Unit\u00e9 Mixte de Recherche (UMR) 1236, Etablissement Fran\u00e7ais du sang Bretagne, Universit\u00e9 Rennes 1, Rennes, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4689-3882","authenticated-orcid":false,"given":"Ga\u00eblle","family":"Drillet","sequence":"additional","affiliation":[{"name":"Service d\u2019H\u00e9matologie Clinique, Centre Hospitalier Universitaire (CHU) de Rennes, Rennes, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Le Gallou","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019H\u00e9matologie, Centre Hospitalier Universitaire de Rennes, 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