{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:34:00Z","timestamp":1771929240823,"version":"3.50.1"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32301234"],"award-info":[{"award-number":["32301234"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010877","name":"Science, Technology and Innovation Commission of Shenzhen Municipality","doi-asserted-by":"publisher","award":["JCYJ20240813172200002"],"award-info":[{"award-number":["JCYJ20240813172200002"]}],"id":[{"id":"10.13039\/501100010877","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012151","name":"Sanming Project of Medicine in Shenzen Municipality","doi-asserted-by":"publisher","award":["SZSM202311032"],"award-info":[{"award-number":["SZSM202311032"]}],"id":[{"id":"10.13039\/501100012151","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"\n Introduction<\/jats:title>\n \n The killer-cell immunoglobulin-like receptor (\n KIR<\/jats:italic>\n ) gene cluster exhibits complicated diversity in haplotype content, copy-number variation (CNV), and allelic polymorphism. To date, 2,286 distinct\n KIR<\/jats:italic>\n alleles have been released in the IPD-KIR Database. However, little is known about the impact of high-resolution-level\n KIR<\/jats:italic>\n allelic polymorphisms on leukemia. Our previous study showed that the\n KIR AA<\/jats:italic>\n genotype carrying more inhibitory genes conferred differential protection against leukemia in the Chinese Southern Han population. Herein, we hypothesized the impact of\n KIR<\/jats:italic>\n alleles in the\n KIR A<\/jats:italic>\n haplotype and cognate human leukocyte antigen (HLA) ligand on leukemia.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n The study cohort included 318 ALL patients, 336 AML patients, and 306 unrelated healthy controls. All the study samples were subject to\n HLA-A<\/jats:italic>\n , -\n B<\/jats:italic>\n , and -\n C<\/jats:italic>\n sequencing-based genotyping (PCR-SBT) and high-resolution\n KIR<\/jats:italic>\n genotyping for all the seven functional\n KIR<\/jats:italic>\n genes (\n KIR2DL1<\/jats:italic>\n ,\n KIR2DL3<\/jats:italic>\n ,\n KIR2DL4<\/jats:italic>\n ,\n KIR3DL1<\/jats:italic>\n ,\n KIR3DL2<\/jats:italic>\n ,\n KIR3DL3<\/jats:italic>\n , and\n KIR2DS4<\/jats:italic>\n ) on the\n KIR A<\/jats:italic>\n haplotype.\n HLA<\/jats:italic>\n and\n KIR<\/jats:italic>\n genotypes were assigned using Assign 4.7.1 software.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In the present study, our high-resolution genetic analysis revealed protective\n KIR<\/jats:italic>\n \u2013\n HLA<\/jats:italic>\n interactions in individuals with the\n KIR AA<\/jats:italic>\n genotype. The strong inhibitory\n KIR2DL1*00201<\/jats:italic>\n +\n C2<\/jats:italic>\n interaction reduced ALL risk (\n p<\/jats:italic>\n = 0.01), while\n KIR2DL1*00302<\/jats:italic>\n +\n C2<\/jats:italic>\n (\n p<\/jats:italic>\n = 0.008),\n KIR2DL3*00201<\/jats:italic>\n +\n C1<\/jats:italic>\n (\n p<\/jats:italic>\n = 0.03), and\n KIR3DL1*00501<\/jats:italic>\n +\n Bw4 80I<\/jats:italic>\n (\n p<\/jats:italic>\n = 0.008) interactions protected against AML (\n p<\/jats:italic>\n &lt; 0.05). However, the functionally weaker inhibitory\n KIR2DL1*004<\/jats:italic>\n +\n C2<\/jats:italic>\n interaction conferred ALL risk (\n p<\/jats:italic>\n = 0.01) in individuals with the\n KIR Bx<\/jats:italic>\n genotype. Notably, we found that the allelic polymorphisms of the structure gene\n KIR3DL3<\/jats:italic>\n were associated with the occurrence of leukemia.\n KIR3DL3*001<\/jats:italic>\n tends to confer protection against AML (8.4% vs. 1.3%,\n p<\/jats:italic>\n = 0.004,\n Pc<\/jats:italic>\n = 0.06), whereas\n KIR3DL3*009<\/jats:italic>\n conferred susceptibility to AML (29.3% vs. 47.1%,\n p<\/jats:italic>\n = 0.001,\n Pc =<\/jats:italic>\n 0.016).\n KIR3DL3*001<\/jats:italic>\n differs from\n KIR3DL3*009<\/jats:italic>\n by an amino acid substitution of non-charged asparagine (N) to charged histidine (H) in its transmembrane domain, suggesting that this functional variant site KIR3DL3_N300H may play a critical role in the occurrence of leukemia in the Chinese population.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n These data suggest that\n KIR AA<\/jats:italic>\n individuals possess strong inhibitory interactions of\n KIR<\/jats:italic>\n alleles and\n HLA<\/jats:italic>\n , arming\n KIR AA<\/jats:italic>\n \n +<\/jats:italic>\n <\/jats:sup>\n NK cells to meditate stronger alloreactivity and cytotoxicity against leukemia cells with lowered HLA expression. Our findings may provide valuable insights into leukemia pathogenesis and better understanding of the immune mechanisms.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fgene.2025.1745482","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T22:10:29Z","timestamp":1770243029000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["KIR AA individuals possess strong inhibitory KIR alleles alongside HLA ligands that are protective against leukemia in the Chinese population"],"prefix":"10.3389","volume":"16","author":[{"given":"Zhihui","family":"Deng","sequence":"first","affiliation":[{"name":"Immunogenetics Laboratory, Shenzhen Blood Center","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianxin","family":"Zhen","sequence":"additional","affiliation":[{"name":"Central Laboratory, Shenzhen Baoan Women\u2019s and Children\u2019s Hospital","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunan","family":"Li","sequence":"additional","affiliation":[{"name":"Immunogenetics Laboratory, Shenzhen Blood Center","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuang","family":"Liang","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine, Shenzhen Blood Center","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Immunogenetics Laboratory, Shenzhen Blood Center","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siqi","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Blood Transfusion, The Eighth Affiliated Hospital, Sun Yat-Sen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renhui","family":"Jiang","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine, Shenzhen Blood Center","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhichao","family":"Yang","sequence":"additional","affiliation":[{"name":"Immunogenetics Laboratory, Shenzhen Blood Center","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiong","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine, Shenzhen Blood Center","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinyong","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences","place":["Beijing, China"]},{"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Immunogenetics Laboratory, Shenzhen Blood Center","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4781","DOI":"10.1172\/JCI74337","article-title":"Cytokine therapy reverses NK cell anergy in MHC-deficient tumors","volume":"124","author":"Ardolino","year":"2014","journal-title":"J. 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