{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:55:48Z","timestamp":1790920548494,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cytometry Part B Clinical"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Accurate immunophenotypic evaluation of natural killer (NK)\u2010cell neoplasms is challenging because NK\u2010cells lack somatically rearranged antigen receptors, are comprised of phenotypically distinct subsets, and exhibit tissue\u2010specific subset distribution. We developed a flow cytometry (FC) panel for NK\u2010cell immunophenotypic analysis and clonality assessment and applied it to 120 specimens, including normal peripheral blood (PB), bone marrow (BM), lymph node (LN), and body fluids, as well as a series of NK\u2010cell neoplasms and NK\u2010cell clones of uncertain significance (NK\u2010CUS). The expression ranges for NK\u2010cell receptors (NKR) including killer immunoglobulin\u2010like receptors (KIR, CD158) in the PB were consistent with those reported previously by other groups. The distribution of NK\u2010cell subsets differed by the specimen type. While PB and BM NK\u2010cells showed predominance of the CD56\n                    <jats:sup>dim<\/jats:sup>\n                    subset, LN and fluid samples were enriched for the CD56\n                    <jats:sup>bright<\/jats:sup>\n                    subset, resulting in higher CD94\/NKG2A and lower KIR expression compared to PB. Epstein\u2013Barr\u2010virus (EBV)\u2010positive NK\/T\u2010cell neoplasms exhibited a relatively consistent CD56\n                    <jats:sup>bright<\/jats:sup>\n                    CD16\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD94\/NKG2A\n                    <jats:sup>+<\/jats:sup>\n                    CD57\n                    <jats:sup>\u2212<\/jats:sup>\n                    KIR\n                    <jats:sup>\u2212<\/jats:sup>\n                    immunophenotype that resembled normal CD56\n                    <jats:sup>bright<\/jats:sup>\n                    NK\u2010cells, emphasizing the importance of immunophenotypic aberrancies and increased scatter properties rather than restricted KIR expression in diagnosing such neoplasms. NK\u2010large granular lymphocytic leukemia (NK\u2010LGLL) demonstrated a mature CD56\n                    <jats:sup>dim<\/jats:sup>\n                    phenotype with restricted KIR expression. Twelve cases fulfilled the proposed criteria for NK\u2010CUS, comprising both putative cytomegalovirus (CMV)\u2010related NK\u2010cell clones and phenotypically distinct (likely) CMV\u2010unrelated clones with more pronounced immunophenotypic abnormalities. Our findings suggest that interpretation of NK\u2010cell clonality should take into account NK\u2010cell subset composition and tissue\u2010specific receptor expression. These results provide practical considerations for NK\u2010cell immunophenotypic analysis and contribute to a better understanding of the role of FC in diagnosing such neoplasms.\n                  <\/jats:p>","DOI":"10.1002\/cyto.b.70078","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:39:21Z","timestamp":1790919561000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Subset\u2010specific and tissue\u2010specific expression of\n                    <scp>NK<\/scp>\n                    \u2010cell markers and killer immunoglobulin\u2010like receptors: Implications for\n                    <scp>NK<\/scp>\n                    \u2010cell clonality assessment"],"prefix":"10.1002","author":[{"given":"Valerie","family":"Woodings","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orrin","family":"Koepke","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason E.","family":"Love","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Torabi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4218-4587","authenticated-orcid":false,"given":"Lianqun","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Hematopathology The University of Texas MD Anderson Cancer Center  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Fromm","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sindhu","family":"Cherian","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afshin","family":"Shameli","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"issue":"7","key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the World Health Organization classification of Haematolymphoid Tumours: Lymphoid neoplasms","volume":"36","author":"Alaggio R.","year":"2022","journal-title":"Leukemia"},{"issue":"5","key":"e_1_2_8_3_1","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/s41588-022-01059-2","article-title":"CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk","volume":"54","author":"Baer C.","year":"2022","journal-title":"Nat Genet"},{"issue":"14","key":"e_1_2_8_4_1","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1182\/blood-2012-10-459545","article-title":"NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs","volume":"121","author":"Beziat V.","year":"2013","journal-title":"Blood"},{"issue":"5","key":"e_1_2_8_5_1","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/nri.2016.34","article-title":"Emerging insights into natural killer cells in human peripheral tissues","volume":"16","author":"Bjorkstrom N. K.","year":"2016","journal-title":"Nat Rev Immunol"},{"issue":"19","key":"e_1_2_8_6_1","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1182\/blood-2010-04-281675","article-title":"Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK\u2010cell differentiation uncoupled from NK\u2010cell education","volume":"116","author":"Bjorkstrom N. K.","year":"2010","journal-title":"Blood"},{"issue":"4","key":"e_1_2_8_7_1","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.cell.2020.01.022","article-title":"Tissue determinants of human NK cell development, function, and residence","volume":"180","author":"Dogra P.","year":"2020","journal-title":"Cell"},{"issue":"10","key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1158\/2326-6066.CIR-17-0279","article-title":"IL15 infusion of cancer patients expands the subpopulation of cytotoxic CD56(bright) NK cells and increases NK\u2010cell cytokine release capabilities","volume":"5","author":"Dubois S.","year":"2017","journal-title":"Cancer Immunol Res"},{"issue":"3","key":"e_1_2_8_9_1","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1136\/jcp.54.3.224","article-title":"Expression of killer cell inhibitory receptors is restricted to true NK cell lymphomas and a subset of intestinal enteropathy\u2010type T cell lymphomas with a cytotoxic phenotype","volume":"54","author":"Dukers D. F.","year":"2001","journal-title":"J Clin Pathol"},{"issue":"3","key":"e_1_2_8_10_1","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.4049\/jimmunol.181.3.2227","article-title":"An unusual CD56(bright) CD16(low) NK cell subset dominates the early posttransplant period following HLA\u2010matched hematopoietic stem cell transplantation","volume":"181","author":"Dulphy N.","year":"2008","journal-title":"J Immunol"},{"issue":"11","key":"e_1_2_8_11_1","doi-asserted-by":"crossref","first-page":"3628","DOI":"10.1182\/blood.V95.11.3628","article-title":"Expression of CD94\/NKG2A and killer immunoglobulin\u2010like receptors in NK cells and a subset of extranodal cytotoxic T\u2010cell lymphomas","volume":"95","author":"Haedicke W.","year":"2000","journal-title":"Blood"},{"issue":"2","key":"e_1_2_8_12_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1002\/cyto.b.21768","article-title":"Flow cytometry applications in the diagnosis of T\/NK\u2010cell lymphoproliferative disorders","volume":"96","author":"Jevremovic D.","year":"2019","journal-title":"Cytometry B Clin Cytom"},{"issue":"6","key":"e_1_2_8_13_1","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.smim.2008.06.003","article-title":"The yin and Yang of HLA and KIR in human disease","volume":"20","author":"Kulkarni S.","year":"2008","journal-title":"Semin Immunol"},{"key":"e_1_2_8_14_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.smim.2022.101706","article-title":"Adaptive NK cell response to human cytomegalovirus: Facts and open issues","volume":"65","author":"Lopez\u2010Botet M.","year":"2023","journal-title":"Semin Immunol"},{"issue":"2","key":"e_1_2_8_15_1","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.jaci.2022.09.022","article-title":"Human natural killer cells: Form, function, and development","volume":"151","author":"Mace E. M.","year":"2023","journal-title":"J Allergy Clin Immunol"},{"key":"e_1_2_8_16_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2016.00262","article-title":"Human circulating and tissue\u2010resident CD56(bright) natural killer cell populations","volume":"7","author":"Melsen J. E.","year":"2016","journal-title":"Front Immunol"},{"issue":"1","key":"e_1_2_8_17_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1053\/j.semdp.2019.12.004","article-title":"Epstein \u2010 Barr virus positive T and NK\u2010cell lymphoproliferations: Morphological features and differential diagnosis","volume":"37","author":"Montes\u2010Mojarro I. A.","year":"2020","journal-title":"Semin Diagn Pathol"},{"issue":"4","key":"e_1_2_8_18_1","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/leu.2009.304","article-title":"Chronic lymphoproliferative disorder of natural killer cells: A distinct entity with subtypes correlating with normal natural killer cell subsets","volume":"24","author":"Morice W. G.","year":"2010","journal-title":"Leukemia"},{"issue":"6","key":"e_1_2_8_19_1","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1002\/cyto.b.22258","article-title":"A practical approach to panel design, validation, and interpretation for the evaluation of T\u2010cell neoplasms by flow cytometry","volume":"108","author":"Oak J.","year":"2025","journal-title":"Cytometry B Clin Cytom"},{"issue":"23","key":"e_1_2_8_20_1","doi-asserted-by":"crossref","first-page":"3237","DOI":"10.1182\/blood.2020006721","article-title":"Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells","volume":"137","author":"Pastoret C.","year":"2021","journal-title":"Blood"},{"issue":"3","key":"e_1_2_8_21_1","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1182\/bloodadvances.2025016509","article-title":"Diagnostic criteria for NK cell large granular lymphocyte leukemia: Validation through a multicentric international study","volume":"10","author":"Pastoret C.","year":"2026","journal-title":"Blood Adv"},{"issue":"4","key":"e_1_2_8_22_1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1111\/j.1365-2567.2008.03027.x","article-title":"CD56bright natural killer (NK) cells: An important NK cell subset","volume":"126","author":"Poli A.","year":"2009","journal-title":"Immunology"},{"issue":"3","key":"e_1_2_8_23_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.4161\/cbt.27310","article-title":"Large granular lymphocytosis during dasatinib therapy","volume":"15","author":"Qiu Z. Y.","year":"2014","journal-title":"Cancer Biol Ther"},{"issue":"8","key":"e_1_2_8_24_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.modpat.2023.100255","article-title":"Establishing NK\u2010cell receptor restriction by flow cytometry and detecting potential NK\u2010cell clones of uncertain significance","volume":"36","author":"Seheult J. N.","year":"2023","journal-title":"Mod Pathol"},{"issue":"6","key":"e_1_2_8_25_1","article-title":"NK\u2010type large granular lymphocyte leukemia comes of age","volume":"9","author":"Semenzato G.","year":"2025","journal-title":"Hema"},{"issue":"5","key":"e_1_2_8_26_1","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1093\/ajcp\/aqae064","article-title":"How I diagnose large granular lymphocytic leukemia","volume":"162","author":"Shi M.","year":"2024","journal-title":"Am J Clin Pathol"},{"issue":"5","key":"e_1_2_8_27_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.modpat.2026.100984","article-title":"NKG2C improves diagnostic specificity of natural killer (NK) cell receptor restriction by identifying nonneoplastic adaptive NK cell clones","volume":"39","author":"Wilk A. J.","year":"2026","journal-title":"Mod Pathol"},{"issue":"5","key":"e_1_2_8_28_1","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1182\/blood-2002-12-3898","article-title":"Expression and function of KIR and natural cytotoxicity receptors in NK\u2010type lymphoproliferative diseases of granular lymphocytes","volume":"102","author":"Zambello R.","year":"2003","journal-title":"Blood"}],"container-title":["Cytometry Part B: Clinical Cytometry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cyto.b.70078","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cyto.b.70078","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cyto.b.70078","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:39:25Z","timestamp":1790919565000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cyto.b.70078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":27,"alternative-id":["10.1002\/cyto.b.70078"],"URL":"https:\/\/doi.org\/10.1002\/cyto.b.70078","archive":["Portico"],"relation":{},"ISSN":["1552-4949","1552-4957"],"issn-type":[{"value":"1552-4949","type":"print"},{"value":"1552-4957","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"assertion":[{"value":"2026-07-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cyto.b.70078"}}