{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T03:47:23Z","timestamp":1777520843878,"version":"3.51.4"},"reference-count":86,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Scientific Research Project of Hunan Provincial Health Commission","award":["20200759"],"award-info":[{"award-number":["20200759"]}]},{"name":"Scientific Research Project of Hunan Provincial Health Commission","award":["20200759"],"award-info":[{"award-number":["20200759"]}]},{"name":"Scientific Research Project of Hunan Provincial Health Commission","award":["20200759"],"award-info":[{"award-number":["20200759"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cancer Res Clin Oncol"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Currently, the significance of <jats:italic>CDKN2A\/B<\/jats:italic> mutations in the pathogenesis and prognosis of acute lymphoblastic leukemia (ALL) is inconclusive. In this study, we analyzed the genetic and clinical features of children with <jats:italic>CDKN2A\/B<\/jats:italic> mutations in ALL. In addition, we evaluated the expression and significance of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in serum and explored their role in the susceptibility of childhood ALL.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We sequenced <jats:italic>CDKN2A\/B<\/jats:italic> in the peripheral blood of 120 children with ALL and 100 healthy children with physical examination. The levels of CD4<jats:sup>+<\/jats:sup> T, CD8<jats:sup>+<\/jats:sup> T, and NK cells were measured by flow cytometry (FCM). Furthermore, the expression of PD-1 and PD-L1 was detected by ELISA.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found 32 cases of <jats:italic>CDKN2A<\/jats:italic> rs3088440 and 11 of <jats:italic>CDKN2B<\/jats:italic> rs2069426 in 120 ALL children. Children with ALL in the <jats:italic>CDKN2A<\/jats:italic> rs3088440 were more likely to have hepatosplenomegaly (<jats:italic>P<\/jats:italic>\u2009=\u20090.019) and high risk (<jats:italic>P<\/jats:italic>\u2009=\u20090.014) than the wild group. In contrast, <jats:italic>CDKN2B<\/jats:italic> rs2069426 was more likely to develop lymph node metastasis (<jats:italic>P<\/jats:italic>\u2009=\u20090.017). The level of PD-L1 in the serum of ALL children was significantly higher than that of the control group, and there was no significant difference in PD-1 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). Additionally, children with <jats:italic>CDKN2A<\/jats:italic> rs3088440 had reduced CD8<jats:sup>+<\/jats:sup> T cell counts than the wild group (<jats:italic>P<\/jats:italic>\u2009=\u20090.039).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p><jats:italic>CDKN2A<\/jats:italic> rs3088440 and <jats:italic>CDKN2B<\/jats:italic> rs2069426 may be related to the occurrence and development of ALL in Chinese children. Additionally, PD-1\/PD-L1 may be involved in the immune escape process of ALL, which is expected to become a new target for the treatment of the disease.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00432-023-04974-x","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T13:02:05Z","timestamp":1686747725000},"page":"10841-10850","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Association of CDKN2A\/B mutations, PD-1, and PD-L1 with the risk of acute lymphoblastic leukemia in children"],"prefix":"10.1007","volume":"149","author":[{"given":"Yang","family":"Ruan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Longlong","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aijun","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"4974_CR1","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1089\/gtmb.2017.0084","volume":"21","author":"B Al-Absi","year":"2017","unstructured":"Al-Absi B, Razif MFM, Noor SM et al (2017) Contributions of IKZF1, DDC, CDKN2A, CEBPE, and LMO1 gene polymorphisms to acute lymphoblastic leukemia in a Yemeni population. Genet Test Mol Biomark 21:592\u2013599. https:\/\/doi.org\/10.1089\/gtmb.2017.0084","journal-title":"Genet Test Mol Biomark"},{"key":"4974_CR2","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1186\/s12920-022-01325-6","volume":"15","author":"MS Bardsiri","year":"2022","unstructured":"Bardsiri MS, Zehtab S, Karami N et al (2022) Association of IKZF1 and CDKN2A gene polymorphisms with childhood acute lymphoblastic leukemia: a high-resolution melting analysis. BMC Med Genom 15:171. https:\/\/doi.org\/10.1186\/s12920-022-01325-6","journal-title":"BMC Med Genom"},{"key":"4974_CR3","doi-asserted-by":"publisher","unstructured":"Bian B, Fanale D, Dusetti N et al (2019) Prognostic signifificance of circulating PD-1, PD-L1, pan-BTN3As, BTN3A1 and BTLA in patients with pancreatic adenocarcinoma. Oncoimmunology 8:e1561120. https:\/\/doi.org\/10.1080\/2162402X.2018.1561120","DOI":"10.1080\/2162402X.2018.1561120"},{"key":"4974_CR4","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1080\/10428194.2016.1228925","volume":"58","author":"M Braun","year":"2017","unstructured":"Braun M, Pastorczak A, Fendler W et al (2017) Biallelic loss of CDKN2A is associated with poor response to treatment in pediatric acute lymphoblastic leukemia. Leuk Lymphoma 58:1162\u20131171. https:\/\/doi.org\/10.1080\/10428194.2016.1228925","journal-title":"Leuk Lymphoma"},{"key":"4974_CR5","doi-asserted-by":"publisher","first-page":"2761","DOI":"10.1091\/mbc.E14-05-0966","volume":"25","author":"EMC Britigan","year":"2014","unstructured":"Britigan EMC, Wan J, Zasadil LM et al (2014) The ARF tumor suppressor prevents chromosomal instability and ensures mitotic checkpoint fidelity through regulation of Aurora B. Mol Biol Cell 25:2761\u20132773. https:\/\/doi.org\/10.1091\/mbc.E14-05-0966","journal-title":"Mol Biol Cell"},{"key":"4974_CR6","doi-asserted-by":"publisher","unstructured":"Burd CE, Jeck WR, Liu Y et al (2010) Expression of linear and novel circular forms of an INK4\/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet 6:e1001233. https:\/\/doi.org\/10.1371\/journal.pgen.1001233","DOI":"10.1371\/journal.pgen.1001233"},{"key":"4974_CR7","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1038\/s41375-018-0097-x","volume":"32","author":"MA Burns","year":"2018","unstructured":"Burns MA, Liao ZW, Yamagata N et al (2018) Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia. Leukemia 32:2126\u20132137. https:\/\/doi.org\/10.1038\/s41375-018-0097-x","journal-title":"Leukemia"},{"key":"4974_CR8","doi-asserted-by":"publisher","first-page":"79","DOI":"10.3390\/genes12010079","volume":"12","author":"GG Celia","year":"2021","unstructured":"Celia GG, Jordi R, Josep MR et al (2021) The yin and yang-like clinical implications of the CDKN2A\/ARF\/CDKN2B gene cluster in acute lymphoblastic leukemia. Genes 12:79. https:\/\/doi.org\/10.3390\/genes12010079","journal-title":"Genes"},{"key":"4974_CR9","doi-asserted-by":"publisher","first-page":"213","DOI":"10.5414\/NP301022","volume":"36","author":"AK Chan","year":"2017","unstructured":"Chan AK, Han SJ, Choy W et al (2017) Familial melanoma-astrocytoma syndrome: synchronous diffuse astrocytoma and pleomorphic xanthoastrocytoma in a patient with germline CDKN2A\/B deletion and a significant family history. Clin Neuropathol 36:213\u2013221. https:\/\/doi.org\/10.5414\/NP301022","journal-title":"Clin Neuropathol"},{"key":"4974_CR10","doi-asserted-by":"publisher","unstructured":"Chang B, Huang T, Wei H et al (2019) The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma. Cancer Immunol Immunother 68:353\u2013363. https:\/\/doi.org\/10.1007\/s00262-018-2271-4","DOI":"10.1007\/s00262-018-2271-4"},{"key":"4974_CR11","doi-asserted-by":"publisher","unstructured":"Chen YC,\u00a0Gotea V,\u00a0Margolin G et al (2017) Significant associations between driver gene mutations and DNA methylation alterations across many cancer types.\u00a0PLoS Comput Biol 13: e1005840. https:\/\/doi.org\/10.1371\/journal.pcbi.1005840","DOI":"10.1371\/journal.pcbi.1005840"},{"key":"4974_CR12","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1158\/1535-7163.MCT-16-0501","volume":"16","author":"E Cocco","year":"2017","unstructured":"Cocco E, Deng Y, Shapiro EM et al (2017) Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy resistant ovarian cancer cells. Mol Cancer Ther 16:323\u2013333. https:\/\/doi.org\/10.1158\/1535-7163.MCT-16-0501","journal-title":"Mol Cancer Ther"},{"key":"4974_CR13","doi-asserted-by":"publisher","unstructured":"Deng W, Xu Y, Yuan X (2022) Clinical features and prognosis of acute lymphoblastic leukemia in children with Epstein-Barr virus infection. Transl Pediatr 11: 642\u2013650. https:\/\/doi.org\/10.21037\/tp-22-146","DOI":"10.21037\/tp-22-146"},{"key":"4974_CR14","doi-asserted-by":"publisher","unstructured":"Dong Y, Wang X, Yang YW et al (2017) The efects of CDKN2A rs3731249, rs11515, and rs3088440 polymorphisms on cancer risk. Cell Mol Biol 63:40\u201344. https:\/\/doi.org\/10.14715\/cmb\/2017.63.3.8","DOI":"10.14715\/cmb\/2017.63.3.8"},{"key":"4974_CR15","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1002\/1097-0142(19860301)57:5<1046::aid-cncr2820570529>3.0.co;2-0","volume":"57","author":"J Eys","year":"1986","unstructured":"Eys J, Pullen J, Head D et al (1986) The French-American-British (FAB) classification of leukemia. The pediatric oncology group experience with lymphocytic leukemia. Cancer 57:1046\u20131051. https:\/\/doi.org\/10.1002\/1097-0142(19860301)57:5%3c1046::aid-cncr2820570529%3e3.0.co;2-0","journal-title":"Cancer"},{"key":"4974_CR16","doi-asserted-by":"publisher","first-page":"8509","DOI":"10.1002\/jcp.27782","volume":"234","author":"B Farhood","year":"2019","unstructured":"Farhood B, Najafi M, Mortezaee K (2019) CD8+ cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol 234:8509\u20138521. https:\/\/doi.org\/10.1002\/jcp.27782","journal-title":"J Cell Physiol"},{"key":"4974_CR17","doi-asserted-by":"publisher","first-page":"370","DOI":"10.3390\/jpm12030370","volume":"12","author":"MR Fernandes","year":"2022","unstructured":"Fernandes MR, Souza Vinagre LWM, Rodrigues JCG et al (2022) Correlation of genetic variants and the incidence, prevalence and mortality rates of acute lymphoblastic leukemia. J Pers Med 12:370. https:\/\/doi.org\/10.3390\/jpm12030370","journal-title":"J Pers Med"},{"key":"4974_CR18","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1084\/jem.192.7.1027","volume":"192","author":"GJ Freeman","year":"2000","unstructured":"Freeman GJ, Long AJ, Iwai Y et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027\u20131034. https:\/\/doi.org\/10.1084\/jem.192.7.1027","journal-title":"J Exp Med"},{"key":"4974_CR19","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.imlet.2011.11.001","volume":"142","author":"X Frigola","year":"2012","unstructured":"Frigola X, Inman BA, Krco CJ et al (2012) Soluble B7\u2013H1: differences in production between dendritic cells and T cells. Immunol Lett 142:78\u201382. https:\/\/doi.org\/10.1016\/j.imlet.2011.11.001","journal-title":"Immunol Lett"},{"key":"4974_CR20","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1016\/j.celrep.2017.07.075","volume":"20","author":"M Gato-Canas","year":"2017","unstructured":"Gato-Canas M, Zuazo M, Arasanz H et al (2017) PDL1 signals through conserved sequence motifs to overcome inter feron-mediated cytotoxicity. Cell Rep 20:1818\u20131829. https:\/\/doi.org\/10.1016\/j.celrep.2017.07.075","journal-title":"Cell Rep"},{"key":"4974_CR21","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1007\/s13277-013-1097-0","volume":"35","author":"LM Guo","year":"2014","unstructured":"Guo LM, Xi JS, Ma Y et al (2014) ARID5B gene rs10821936 polymorphism is associated with childhood acute lymphoblastic leukemia: a meta-analysis based on 39,116 subjects. Tumor Biol 35:709\u2013713. https:\/\/doi.org\/10.1007\/s13277-013-1097-0","journal-title":"Tumor Biol"},{"key":"4974_CR22","doi-asserted-by":"publisher","unstructured":"Gutierrez-Camino A, Martin-Guerrero I, Andoin NG et al (2017) Confirmation of involvement of new variants at CDKN2A\/B in pediatric acute lymphoblastic leukemia susceptibility in the Spanish population. PLoS One 12:e0177421. https:\/\/doi.org\/10.1371\/journal.pone.0177421","DOI":"10.1371\/journal.pone.0177421"},{"key":"4974_CR23","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nature22071","volume":"545","author":"NK Hayward","year":"2017","unstructured":"Hayward NK, Wilmott JS, Waddell N et al (2017) Whole genome landscapes of major melanoma subtypes. Nature 545:175\u2013180. https:\/\/doi.org\/10.1038\/nature22071","journal-title":"Nature"},{"key":"4974_CR24","doi-asserted-by":"publisher","unstructured":"Healy J, B\u00e9langer H, Beaulieu P et al (2007) Promoter SNPs in G1\/S checkpoint regulators and their impact on the susceptibility to childhood leukemia. Blood 109:683\u2013692. https:\/\/doi.org\/10.1182\/blood-2006-02-003236","DOI":"10.1182\/blood-2006-02-003236"},{"key":"4974_CR25","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.critrevonc.2019.08.009","volume":"143","author":"TA Hejleh","year":"2019","unstructured":"Hejleh TA, Muhammad Furqan M, Ballas Z et al (2019) The clinical signifificance of soluble PD-1 and PD-L1 in lung cancer. Crit Rev Oncol Hematol 143:148\u2013152. https:\/\/doi.org\/10.1016\/j.critrevonc.2019.08.009","journal-title":"Crit Rev Oncol Hematol"},{"key":"4974_CR26","doi-asserted-by":"publisher","first-page":"2090","DOI":"10.1002\/jcb.27517","volume":"120","author":"A Hesari","year":"2019","unstructured":"Hesari A, Maleksabet A, Tirkani AN et al (2019) Evaluation of the two polymorphisms rs1801133 in MTHFR and rs10811661 in CDKN2A\/B in breast cancer. J Cell Biochem 120:2090\u20132097. https:\/\/doi.org\/10.1002\/jcb.27517","journal-title":"J Cell Biochem"},{"key":"4974_CR27","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1158\/1055-9965.EPI-15-0528","volume":"25","author":"LI Hsu","year":"2016","unstructured":"Hsu LI, Briggs F, Shao X et al (2016) Pathway analysis of genome-wide association study in childhood leukemia among hispanics. Cancer Epidemiol Biomark Prev 25:815\u2013822. https:\/\/doi.org\/10.1158\/1055-9965.EPI-15-0528","journal-title":"Cancer Epidemiol Biomark Prev"},{"key":"4974_CR28","doi-asserted-by":"publisher","unstructured":"Hui L, Chen Y (2015) Tumor microenvironment: sanctuary of the devil. Cancer Lett 368:7\u201313. https:\/\/doi.org\/10.1016\/j.canlet.2015.07.039","DOI":"10.1016\/j.canlet.2015.07.039"},{"key":"4974_CR29","doi-asserted-by":"publisher","unstructured":"Hungate EA, Vora SR, Gamazon ER et al (2016) A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology. Nat Commun 7:10635. https:\/\/doi.org\/10.1038\/ncomms10635","DOI":"10.1038\/ncomms10635"},{"key":"4974_CR30","doi-asserted-by":"publisher","unstructured":"Imai K (2017) Acute lymphoblastic leukemia: pathophysiology and current therapy. Rinsho Ketsueki 58:460\u2013470.\u00a0https:\/\/doi.org\/10.11406\/rinketsu.58.460","DOI":"10.11406\/rinketsu.58.460"},{"key":"4974_CR31","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12929-017-0329-9","volume":"24","author":"Y Iwai","year":"2017","unstructured":"Iwai Y, Hamanishi J, Chamoto K et al (2017) Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 24:26. https:\/\/doi.org\/10.1186\/s12929-017-0329-9","journal-title":"J Biomed Sci"},{"key":"4974_CR32","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.lungcan.2016.10.015","volume":"102","author":"J Jiang","year":"2016","unstructured":"Jiang J, Gu Y, Liu J et al (2016) Coexistence of p16\/CDKN2A homozygous deletions and activating EGFR mutations in lung adenocarcinoma patients signifies a poor response to EGFR-TKIs. Lung Cancer 102:101\u2013107. https:\/\/doi.org\/10.1016\/j.lungcan.2016.10.015","journal-title":"Lung Cancer"},{"key":"4974_CR33","doi-asserted-by":"publisher","first-page":"204062072092757","DOI":"10.1177\/2040620720927575","volume":"11","author":"SE Karol","year":"2020","unstructured":"Karol SE, Pui CH (2020) Personalized therapy in pediatric high-risk B-cell acute lymphoblastic leukemia. Ther Adv Hematol 11:2040620720927575. https:\/\/doi.org\/10.1177\/2040620720927575","journal-title":"Ther Adv Hematol"},{"key":"4974_CR34","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1080\/10428194.2018.1482542","volume":"60","author":"M Kathiravan","year":"2019","unstructured":"Kathiravan M, Singh M, Bhatia P et al (2019) Deletion of CDKN2A\/B is associated with inferior relapse free survival in pediatric B cell acute lymphoblastic leukemia. Leuk Lymphoma 60:433\u2013441. https:\/\/doi.org\/10.1080\/10428194.2018.1482542","journal-title":"Leuk Lymphoma"},{"key":"4974_CR35","doi-asserted-by":"publisher","unstructured":"Khan M, Zhao Z, Arooj S et al (2020) Soluble PD-1: predictive, prognostic, and therapeutic value for cancer immunotherapy. Front Immunol 11:587460. https:\/\/doi.org\/10.3389\/fimmu.2020.587460","DOI":"10.3389\/fimmu.2020.587460"},{"key":"4974_CR36","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/nrg.2015.17","volume":"17","author":"E Khurana","year":"2016","unstructured":"Khurana E, Fu Y, Chakravarty D et al (2016) Role of non-coding sequence variants in cancer. Nat Rev Genet 17:93\u2013108. https:\/\/doi.org\/10.1038\/nrg.2015.17","journal-title":"Nat Rev Genet"},{"key":"4974_CR37","doi-asserted-by":"publisher","first-page":"2193","DOI":"10.1182\/blood-2015-02-629600","volume":"126","author":"J Kiyasu","year":"2015","unstructured":"Kiyasu J, Miyoshi H, Hirata A et al (2015) Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffffuse large B-cell lymphoma. Blood 126:2193\u20132201. https:\/\/doi.org\/10.1182\/blood-2015-02-629600","journal-title":"Blood"},{"key":"4974_CR38","doi-asserted-by":"publisher","first-page":"158","DOI":"10.3324\/haematol.2009.007526","volume":"95","author":"D Krieger","year":"2010","unstructured":"Krieger D, Moericke A, Oschlies I et al (2010) Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A\/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia. Haematologica 95:158\u2013162. https:\/\/doi.org\/10.3324\/haematol.2009.007526","journal-title":"Haematologica"},{"key":"4974_CR39","doi-asserted-by":"publisher","unstructured":"Kruger S, Legenstein ML, R\u00f6sgen V et al (2017) Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer. Oncoimmunology 6:e1310358. https:\/\/doi.org\/10.1080\/2162402X.2017.1310358","DOI":"10.1080\/2162402X.2017.1310358"},{"key":"4974_CR40","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/hon.3030","volume":"40","author":"S Kumari","year":"2022","unstructured":"Kumari S, Ali MS, Singh J et al (2022) Prognostic utility of key copy number alterations in T cell acute lymphoblastic leukemia. Hematol Oncol 40:577\u2013587. https:\/\/doi.org\/10.1002\/hon.3030","journal-title":"Hematol Oncol"},{"key":"4974_CR41","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1097\/FPC.0000000000000451","volume":"32","author":"C Li","year":"2022","unstructured":"Li C, Zhao X, He Y et al (2022) The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia. Pharmacogenet Genom 32:43\u201350. https:\/\/doi.org\/10.1097\/FPC.0000000000000451","journal-title":"Pharmacogenet Genom"},{"key":"4974_CR42","doi-asserted-by":"publisher","unstructured":"Liao F, Yin D, Zhang Y et al (2016) Association between PIP4K2A polymorphisms and acute lymphoblastic leukemia susceptibility. Medicine (Baltimore) 95:e3542. https:\/\/doi.org\/10.1097\/MD.0000000000003542","DOI":"10.1097\/MD.0000000000003542"},{"key":"4974_CR43","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1038\/s41591-019-0564-6","volume":"25","author":"RG Majzner","year":"2019","unstructured":"Majzner RG, Mackall CL (2019) Clinical lessons learned from the first leg of the CAR T cell journey. Nat Med 25:1341\u20131355. https:\/\/doi.org\/10.1038\/s41591-019-0564-6","journal-title":"Nat Med"},{"key":"4974_CR44","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41580-021-00404-3","volume":"23","author":"HK Matthews","year":"2022","unstructured":"Matthews HK, Bertoli C, Bruin RAM (2022) Cell cycle control in cancer. Nat Rev Mol Cell Biol 23:74\u201388. https:\/\/doi.org\/10.1038\/s41580-021-00404-3","journal-title":"Nat Rev Mol Cell Biol"},{"key":"4974_CR45","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1182\/blood-2014-06-580480","volume":"125","author":"SL Maude","year":"2015","unstructured":"Maude SL, Dolai S, Delgado-Martin C et al (2015) Efficacy of JAK\/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. Blood 125:1759\u20131767. https:\/\/doi.org\/10.1182\/blood-2014-06-580480","journal-title":"Blood"},{"issue":"2","key":"4974_CR46","doi-asserted-by":"publisher","first-page":"473","DOI":"10.3390\/cancers12020473","volume":"12","author":"TM Meyo","year":"2020","unstructured":"Meyo TM, Jouinot A, Giroux-Leprieur E et al (2020) Predictive value of soluble PD-1, PD-L1, VEGFA, CD40 ligand and CD44 for nivolumab therapy in advanced non-small cell lung cancer: a case control study. Cancers (basel) 12(2):473. https:\/\/doi.org\/10.3390\/cancers12020473","journal-title":"Cancers (basel)"},{"key":"4974_CR47","doi-asserted-by":"publisher","unstructured":"Minton K (2020) Overcoming CAR T cell exhaustion. Nat Rev Immunol 20:72\u201373. https:\/\/doi.org\/10.1038\/s41577-019-0265-x","DOI":"10.1038\/s41577-019-0265-x"},{"key":"4974_CR48","first-page":"881","volume":"91","author":"D Mirebeau","year":"2006","unstructured":"Mirebeau D, Acquaviva C, Suciu S et al (2006) The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood: results of the EORTC studies 58881 and 58951. Haematologica 91:881\u2013885","journal-title":"Haematologica"},{"key":"4974_CR49","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1182\/blood-2016-02-698936","volume":"128","author":"H Miyoshi","year":"2016","unstructured":"Miyoshi H, Kiyasu J, Kato T et al (2016) PD-L1 expression on neoplastic or stromal cell is respectively poor or good prognostic factor for adult T-cell leukemia\/lymphoma. Blood 128:1374\u20131381. https:\/\/doi.org\/10.1182\/blood-2016-02-698936","journal-title":"Blood"},{"key":"4974_CR50","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1038\/leu.2009.18","volume":"23","author":"CG Mullighan","year":"2009","unstructured":"Mullighan CG, Downing JR (2009) Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions. Leukemia 23:1209\u20131218. https:\/\/doi.org\/10.1038\/leu.2009.18","journal-title":"Leukemia"},{"key":"4974_CR51","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/s13045-017-0474-3","volume":"10","author":"CY Ok","year":"2017","unstructured":"Ok CY, Young KH (2017) Checkpoint inhibitors in hematological malignancies. J Hematol Oncol 10:103. https:\/\/doi.org\/10.1186\/s13045-017-0474-3","journal-title":"J Hematol Oncol"},{"key":"4974_CR52","doi-asserted-by":"publisher","first-page":"382","DOI":"10.3390\/cancers14020382","volume":"14","author":"FM Onyije","year":"2022","unstructured":"Onyije FM, Olsson A, Baaken D et al (2022) Environmental risk factors for childhood acute lymphoblastic leukemia: an umbrella review. Cancers (basel) 14:382. https:\/\/doi.org\/10.3390\/cancers14020382","journal-title":"Cancers (basel)"},{"key":"4974_CR53","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1182\/blood-2009-09-241513","volume":"115","author":"RB Prasad","year":"2010","unstructured":"Prasad RB, Hosking FJ, Vijayakrishnan J et al (2010) Verifification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood 115:1765\u20131767. https:\/\/doi.org\/10.1182\/blood-2009-09-241513","journal-title":"Blood"},{"key":"4974_CR54","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/s41571-018-0136-6","volume":"16","author":"CH Pui","year":"2019","unstructured":"Pui CH, Nichols KE, Yang JJ (2019) Somatic and germline genomics in paediatric acute lymphoblastic leukaemia. Nat Rev Clin Oncol 16:227\u2013240. https:\/\/doi.org\/10.1038\/s41571-018-0136-6","journal-title":"Nat Rev Clin Oncol"},{"key":"4974_CR55","doi-asserted-by":"publisher","unstructured":"Qian M, Zhao X, Devidas M et al (2019) Genome-wide association study of susceptibility loci for T-cell acute lymphoblastic leukemia in children. J Natl Cancer Inst 111:1350\u20131357. https:\/\/doi.org\/10.1093\/jnci\/djz043","DOI":"10.1093\/jnci\/djz043"},{"key":"4974_CR56","doi-asserted-by":"publisher","unstructured":"Qin H, Ding Y, Mujeeb A et al (2017) Tumor microenvironment targeting and responsive peptide-based nanoformulations for improved tumor therapy. Mol Pharmacol 92:219\u201331. https:\/\/doi.org\/10.1124\/mol.116.108084","DOI":"10.1124\/mol.116.108084"},{"key":"4974_CR57","doi-asserted-by":"publisher","unstructured":"Qin T, Zeng Y, Qin G et al (2015) High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget 6:33972\u201333981. https:\/\/doi.org\/10.18632\/oncotarget.5583","DOI":"10.18632\/oncotarget.5583"},{"key":"4974_CR58","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1007\/s00401-018-1837-8","volume":"136","author":"A Reinhardt","year":"2018","unstructured":"Reinhardt A, Stichel D, Schrimpf D et al (2018) Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A\/B and ATRX alterations. Acta Neuropathol 136:273\u2013291. https:\/\/doi.org\/10.1007\/s00401-018-1837-8","journal-title":"Acta Neuropathol"},{"key":"4974_CR59","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1002\/gcc.22486","volume":"56","author":"J Ribera","year":"2017","unstructured":"Ribera J, Zamora L, Morgades M et al (2017) Copy number profiling of adult relapsed B-cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms. Genes Chromosom Cancer 56:810\u2013820. https:\/\/doi.org\/10.1002\/gcc.22486","journal-title":"Genes Chromosom Cancer"},{"key":"4974_CR60","doi-asserted-by":"publisher","first-page":"3939720","DOI":"10.1155\/2019\/3939720","volume":"2019","author":"Y Ruan","year":"2019","unstructured":"Ruan Y, Hu W, Li W et al (2019) Analysis of plasma EBV-DNA and soluble checkpoint proteins in nasopharyngeal carcinoma patients after defifinitive intensity-modulated radiotherapy. BioMed Res Int 2019:3939720. https:\/\/doi.org\/10.1155\/2019\/3939720","journal-title":"BioMed Res Int"},{"key":"4974_CR61","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1080\/08880018.2016.1251518","volume":"33","author":"PC Salas","year":"2016","unstructured":"Salas PC, Fern\u00e1ndez L, Vela M et al (2016) The role of CDKN2A\/B deletions in pediatric acute lymphoblastic leukemia. Pediatr Hematol Oncol 33:415\u2013422. https:\/\/doi.org\/10.1080\/08880018.2016.1251518","journal-title":"Pediatr Hematol Oncol"},{"key":"4974_CR62","doi-asserted-by":"publisher","unstructured":"ShahidSales S, Mehramiz M, Ghasemi F et al (2018) A genetic variant in CDKN2A\/B gene is associated with the increased risk of breast cancer. J Clin Lab Anal 32:e22190. https:\/\/doi.org\/10.1002\/jcla.22190","DOI":"10.1002\/jcla.22190"},{"key":"4974_CR63","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1186\/s12885-018-4670-5","volume":"18","author":"Z Shen","year":"2018","unstructured":"Shen Z, Gu X, Mao W et al (2018) Influence of pre-transplant minimal residual disease on prognosis after Allo-SCT for patients with acute lymphoblastic leukemia: systematic review and meta-analysis. BMC Cancer 18:755. https:\/\/doi.org\/10.1186\/s12885-018-4670-5","journal-title":"BMC Cancer"},{"key":"4974_CR64","doi-asserted-by":"publisher","unstructured":"Sherborne AL, Hosking FJ, Prasad RB et al (2010) Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat Genet 42:492\u2013494. https:\/\/doi.org\/10.1038\/ng.585","DOI":"10.1038\/ng.585"},{"key":"4974_CR65","doi-asserted-by":"publisher","unstructured":"Shimizu K, Sugiura D, Okazaki IM et al (2020) PD-1 imposes qualitative control of cellular transcriptomes in response to T cell activation. Mol Cell 77:937\u2013950. https:\/\/doi.org\/10.1016\/j.molcel.2019.12.012","DOI":"10.1016\/j.molcel.2019.12.012"},{"key":"4974_CR66","doi-asserted-by":"publisher","unstructured":"Stenman G, Andersson MK, Andr\u00e9n Y (2010) New tricks from an old oncogene: gene fusion and copy number alterations of MYB in human cancer. Cell Cycle 9: 2986\u20132995. https:\/\/doi.org\/10.4161\/cc.9.15.12515","DOI":"10.4161\/cc.9.15.12515"},{"key":"4974_CR67","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1182\/blood-2008-07-166801","volume":"113","author":"S Sulong","year":"2009","unstructured":"Sulong S, Moorman AV, Irving JA et al (2009) A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups. Blood 113:100\u2013107. https:\/\/doi.org\/10.1182\/blood-2008-07-166801","journal-title":"Blood"},{"key":"4974_CR68","doi-asserted-by":"publisher","unstructured":"Terwilliger T, Hay MA (2017) Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J 7:e577. https:\/\/doi.org\/10.1038\/bcj.2017.53","DOI":"10.1038\/bcj.2017.53"},{"key":"4974_CR69","doi-asserted-by":"publisher","unstructured":"Tominaga T, Akiyoshi T, Yamamoto N et al (2019) Clinical signifificance of soluble programmed cell death-1 and soluble programmed cell death-ligand 1 in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. PloS One 14:e0212978. https:\/\/doi.org\/10.1371\/journal.pone.0212978","DOI":"10.1371\/journal.pone.0212978"},{"key":"4974_CR70","doi-asserted-by":"publisher","unstructured":"Vijayakrishnan J, Henrion M, Moorman AV et al (2015) The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A. Sci Rep 5:15065. https:\/\/doi.org\/10.1038\/srep15065","DOI":"10.1038\/srep15065"},{"key":"4974_CR71","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/leu.2016.271","volume":"31","author":"J Vijayakrishnan","year":"2017","unstructured":"Vijayakrishnan J, Kumar R, Henrion MYR et al (2017) A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1. Leukemia 31:573\u2013579. https:\/\/doi.org\/10.1038\/leu.2016.271","journal-title":"Leukemia"},{"key":"4974_CR72","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1038\/s41467-018-03178-z","volume":"9","author":"J Vijayakrishnan","year":"2018","unstructured":"Vijayakrishnan J, Studd J, Broderick P et al (2018) Genome-wide association study identififies susceptibility loci for B-cell childhood acute lymphoblastic leukemia. Nat Commun 9:1340. https:\/\/doi.org\/10.1038\/s41467-018-03178-z","journal-title":"Nat Commun"},{"key":"4974_CR73","doi-asserted-by":"publisher","first-page":"4884","DOI":"10.1158\/0008-5472.CAN-15-1105","volume":"75","author":"KM Walsh","year":"2015","unstructured":"Walsh KM, Smith AJ, Hansen HM et al (2015) A heritable missense polymorphism in CDKN2A confers strong risk of childhood acute lymphoblastic leukemia and is preferentially selected during clonal evolution. Cancer Res 75:4884\u20134894. https:\/\/doi.org\/10.1158\/0008-5472.CAN-15-1105","journal-title":"Cancer Res"},{"key":"4974_CR74","doi-asserted-by":"publisher","first-page":"9331","DOI":"10.1073\/pnas.0710441105","volume":"105","author":"L Wang","year":"2008","unstructured":"Wang L, Pino-Lagos K, Vries VC et al (2008) Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci USA 105:9331\u20139336. https:\/\/doi.org\/10.1073\/pnas.0710441105","journal-title":"Proc Natl Acad Sci USA"},{"key":"4974_CR75","doi-asserted-by":"publisher","first-page":"7553","DOI":"10.1038\/ncomms8553","volume":"6","author":"H Xu","year":"2015","unstructured":"Xu H, Zhang H, Yang W et al (2015) Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. Nat Commun 6:7553. https:\/\/doi.org\/10.1038\/ncomms8553","journal-title":"Nat Commun"},{"key":"4974_CR76","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.3892\/ijmm.2017.2972","volume":"39","author":"Y Yamada","year":"2017","unstructured":"Yamada Y, Sakuma J, Takeuchi I et al (2017) Identifification of six polymorphisms as novel susceptibility loci for ischemic or hemorrhagic stroke by exome-wide association studies. Int J Mol Med 39:1477\u20131491. https:\/\/doi.org\/10.3892\/ijmm.2017.2972","journal-title":"Int J Mol Med"},{"key":"4974_CR77","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1002\/1097-0142(19860715)58:2+<598::aid-cncr2820581332>3.0.co;2-c","volume":"58","author":"JL Young Jr","year":"1986","unstructured":"Young JL Jr, Ries LG, Silverberg E et al (1986) Cancer incidence, survival, mortality for children youner than age 15 years. Cancer 58:598\u2013602. https:\/\/doi.org\/10.1002\/1097-0142(19860715)58:2+%3c598::aid-cncr2820581332%3e3.0.co;2-c","journal-title":"Cancer"},{"key":"4974_CR78","doi-asserted-by":"publisher","first-page":"3783","DOI":"10.4049\/jimmunol.1201449","volume":"190","author":"J Yu","year":"2013","unstructured":"Yu J, Du W, Yan F et al (2013) Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol 190:3783\u20133797. https:\/\/doi.org\/10.4049\/jimmunol.1201449","journal-title":"J Immunol"},{"key":"4974_CR79","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nature25015","volume":"553","author":"J Zhang","year":"2018","unstructured":"Zhang J, Bu X, Wang H et al (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91\u201395. https:\/\/doi.org\/10.1038\/nature25015","journal-title":"Nature"},{"key":"4974_CR80","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1080\/07853890.2018.1564359","volume":"51","author":"W Zhang","year":"2019","unstructured":"Zhang W, Kuang P, Liu T (2019) Prognostic significance of CDKN2A\/B deletions in acute lymphoblastic leukaemia: a meta-analysis. Ann Med 51:28\u201340. https:\/\/doi.org\/10.1080\/07853890.2018.1564359","journal-title":"Ann Med"},{"key":"4974_CR81","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.ebiom.2016.04.017","volume":"8","author":"R Zhao","year":"2016","unstructured":"Zhao R, Choi BY, Lee MH et al (2016) Implications of genetic and epigenetic alterations of CDKN2A (p16INK4a) in cancer. EBioMedicine 8:30\u201339. https:\/\/doi.org\/10.1016\/j.ebiom.2016.04.017","journal-title":"EBioMedicine"},{"key":"4974_CR82","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1007\/s11427-019-9665-8","volume":"63","author":"Z Zhao","year":"2020","unstructured":"Zhao Z, Xiao X, Saw PE et al (2020) Chimeric antigen receptor T cells in solid tumors: a war against the tumor microenvironment. Sci China Life Sci 63:180\u2013205. https:\/\/doi.org\/10.1007\/s11427-019-9665-8","journal-title":"Sci China Life Sci"},{"key":"4974_CR83","doi-asserted-by":"crossref","unstructured":"Zhou X, Liao F, Zhang J et al (2018) Association of the independent polymorphisms in CDKN2A with susceptibility of acute lymphoblastic leukemia. Biosci Rep 38:BSR20180331. 10.1042\/BSR20180331","DOI":"10.1042\/BSR20180331"},{"key":"4974_CR84","doi-asserted-by":"publisher","unstructured":"Zhou Y, Miao J, Wu H et al (2017) PD-1 and PD-L1 expression in 132 recurrent nasopharyngeal carcinoma: the correlation with anemia and outcomes. Oncotarget 8:51210\u201351223. https:\/\/doi.org\/10.18632\/oncotarget.17214","DOI":"10.18632\/oncotarget.17214"},{"key":"4974_CR85","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.4161\/onci.21335","volume":"1","author":"L Zitvogel","year":"2012","unstructured":"Zitvogel L, Kroemer G (2012) Targeting PD-1\/PD-L1 interactions for cancer immunotherapy. Oncoimmunology 1:1223\u20131225. https:\/\/doi.org\/10.4161\/onci.21335","journal-title":"Oncoimmunology"},{"key":"4974_CR86","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1038\/sj.leu.2403769","volume":"19","author":"LJ Zutven","year":"2005","unstructured":"Zutven LJ, Drunen E, Bont JM et al (2005) CDKN2 deletions have no prognostic value in childhood precursor-B acute lymphoblastic leukaemia. Leukemia 19:1281\u20131284. https:\/\/doi.org\/10.1038\/sj.leu.2403769","journal-title":"Leukemia"}],"container-title":["Journal of Cancer Research and Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-023-04974-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00432-023-04974-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-023-04974-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,12]],"date-time":"2023-08-12T13:22:46Z","timestamp":1691846566000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00432-023-04974-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,14]]},"references-count":86,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["4974"],"URL":"https:\/\/doi.org\/10.1007\/s00432-023-04974-x","relation":{},"ISSN":["0171-5216","1432-1335"],"issn-type":[{"value":"0171-5216","type":"print"},{"value":"1432-1335","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,14]]},"assertion":[{"value":"3 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 June 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the hospital ethics committee (No. HCHLL-2020-32).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Written informed consent was obtained from all parents.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}