{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:11:51Z","timestamp":1753891911918,"version":"3.41.2"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T00:00:00Z","timestamp":1737417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Natural killer cells, an important component of the innate immune system, can directly recognize and lyse virally infected or transformed cells. However, NK cells fail to restrain the growth of malignancies, such as B-cell acute lymphoblastic leukemia (B-ALL). The molecular genetics of NK cells in the B-ALL bone marrow microenvironment and the mechanisms underlying the inhibited function of NK cells at the single-cell level remain largely elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we studied the frequency and absolute number of NK cells in peripheral blood samples collected from 43 healthy volunteers and 104 pediatric B-ALL patients diagnosed at Hunan Children\u2019s Hospital. We also analyzed published single-cell RNA sequencing (scRNAseq) data from B-ALL and normal bone marrow samples using unsupervised clustering. Our findings were further validated using bulk transcriptomic data and clinical data from a cohort of 139 B-ALL bone marrow samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that the frequency and number of NK cells were significantly decreased in the bone marrow and peripheral blood of B-ALL patients. In-depth analysis of scRNAseq data identified 12 NK cell clusters. Among them, the C2 cluster, which is present in healthy bone marrow but reduced in B-ALL bone marrow, displays overexpression of a transcription factor KLF2 and a significant downregulation of the \u201cleukocyte proliferation\u201d pathway. Furthermore, we found that the expression of KLF2 in B-ALL at diagnosis was positively correlated with the percentage of leukemia cells and the positive rate of minimal residual disease (MRD), indicating that KLF2 is a marker of poor prognosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>There are dramatic differences at the single-cell level in the transcriptomics of NK cells between healthy donors and B-ALL patients. A transcription factor, KLF2, which is enriched in the C2 cluster of NK cells, has been suggested to regulate the proliferation of NK cells and is associated with poor prognosis of pediatric B-ALL.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2024.1456004","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T10:48:26Z","timestamp":1737456506000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcription factor KLF2 is associated with the dysfunctional status of NK cells and the prognosis of pediatric B-ALL patients"],"prefix":"10.3389","volume":"14","author":[{"given":"Fang","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huimin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benshan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.2019.185.issue-6","article-title":"Advances in cellular and humoral immunotherapy - implications for the treatment of poor risk childhood, adolescent, and young adult B-cell non-Hodgkin lymphoma","volume":"185","author":"Chu","year":"2019","journal-title":"Br J haematology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1400972","article-title":"Acute lymphoblastic leukemia in children","volume":"373","author":"Hunger","year":"2015","journal-title":"New Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.1636","article-title":"Childhood acute lymphoblastic leukemia: progress through collaboration","volume":"33","author":"Pui","year":"2015","journal-title":"J Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-022-00491-0","article-title":"Natural killer cells in antitumour adoptive cell immunotherapy","volume":"22","author":"Laskowski","year":"2022","journal-title":"Nat Rev Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s12943-022-01672-z","article-title":"NK cells and solid tumors: therapeutic potential and persisting obstacles","volume":"21","author":"Tong","year":"2022","journal-title":"Mol cancer"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.07.020","article-title":"Natural killer cell deficiency","volume":"132","author":"Orange","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-07-2974","article-title":"Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer","volume":"105","author":"Miller","year":"2005","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39165","article-title":"Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice","volume":"120","author":"Asakura","year":"2010","journal-title":"J Clin Invest"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1016\/j.cell.2019.04.041","article-title":"Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity","volume":"177","author":"Gauthier","year":"2019","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1186\/s12943-020-01238-x","article-title":"Natural killer cells in cancer biology and therapy","volume":"19","author":"Wu","year":"2020","journal-title":"Mol cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.327","article-title":"The TGF-\u03b2\/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia","volume":"30","author":"Rouce","year":"2016","journal-title":"Leukemia"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-006649","article-title":"Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia","volume":"11","author":"Kumar","year":"2023","journal-title":"J immunotherapy Cancer"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.2830300206","article-title":"Studies of the proliferation and differentiation of immature myeloid cells in vitro. 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