{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T10:46:23Z","timestamp":1792406783260,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"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":["Hematological Oncology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:italic>SH2B3<\/jats:italic>\n                    gene, also known as\n                    <jats:italic>LNK<\/jats:italic>\n                    , encodes an adaptor protein that negatively regulates key hematopoietic signaling pathways, including JAK\u2013STAT, MAPK, and PI3K\/AKT, thereby maintaining hematopoietic homeostasis.\n                    <jats:italic>SH2B3<\/jats:italic>\n                    interacts with major signaling regulators such as JAK2, MPL, FLT3, and KIT. Loss\u2010of\u2010function alterations have been reported in several hematologic malignancies, supporting its role as a leukemia predisposition gene. We previously identified a germline start\u2010loss mutation (c.3G\u00a0&gt;\u00a0A) in\n                    <jats:italic>SH2B3<\/jats:italic>\n                    in a family with early\u2010onset myeloproliferative neoplasm, demonstrating that this variant causes\n                    <jats:italic>SH2B3<\/jats:italic>\n                    haploinsufficiency. In the present study, next\u2010generation sequencing of 149 de novo AML patients identified a frequent intronic polymorphism (rs111340708), located within intron 6 (IVS6) of\n                    <jats:italic>SH2B3<\/jats:italic>\n                    . Although this variant has a reported minor allele frequency (MAF) of approximately 12% in European populations, it was enriched in our AML cohort, reaching 34.2% in Core Binding Factor leukemias (CBFLs). The presence of the rs111340708 variant was associated with inferior overall survival, whereas no significant association with progression\u2010free survival was observed. Functional analyses demonstrated that this polymorphism promotes aberrant IVS6 intron retention in AML cells, resulting in reduced abundance of correctly spliced\n                    <jats:italic>SH2B3<\/jats:italic>\n                    transcripts and predicted generation of truncated peptides and\/or nonsense\u2010mediated decay. Consistently, immunoblot analyses of AML patient samples and hematologic cell lines revealed heterogeneous SH2B3 protein expression, including additional SH2B3\u2010immunoreactive species in variant carriers, together with reduced levels of the canonical SH2B3 protein. Collectively, these findings identify a common germline splicing polymorphism as a novel mechanism contributing to\n                    <jats:italic>SH2B3<\/jats:italic>\n                    functional impairment in AML and highlight the potential relevance of non\u2010coding variants in leukemia pathogenesis, with possible implications for risk stratification and future therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1002\/hon.70254","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T17:44:35Z","timestamp":1789235075000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Germline\n                    <i>SH2B3<\/i>\n                    <sup>rs111340708<\/sup>\n                    Splicing Variant Drives Intron Retention and Protein Instability by Impacting Clinical Outcomes in Core Binding Factor AML"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4790-6532","authenticated-orcid":false,"given":"Marta Rachele","family":"Stefanucci","sequence":"first","affiliation":[{"name":"Department of Health Sciences University of Milano  Milano Italy"},{"name":"Department of Hematology and Oncology ASST Grande Ospedale Metropolitano Niguarda  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Leuzzi","sequence":"additional","affiliation":[{"name":"UOC of Hematology ASST Fatebenefratelli Sacco  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Montavoci","sequence":"additional","affiliation":[{"name":"Department of Health Sciences University of Milano  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8771-5428","authenticated-orcid":false,"given":"Davide Paolo","family":"Bernasconi","sequence":"additional","affiliation":[{"name":"Bicocca Bioinformatics Biostatistics and Bioimaging Centre University of Milano\u2010Bicocca  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8196-8174","authenticated-orcid":false,"given":"Luca","family":"Cimaschi","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology ASST Grande Ospedale Metropolitano Niguarda  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7659-2968","authenticated-orcid":false,"given":"Alessandra","family":"Trojani","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology ASST Grande Ospedale Metropolitano Niguarda  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6140-6969","authenticated-orcid":false,"given":"Anna","family":"Caretti","sequence":"additional","affiliation":[{"name":"Department of Health Sciences University of Milano  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Del Castello","sequence":"additional","affiliation":[{"name":"Bicocca Bioinformatics Biostatistics and Bioimaging Centre University of Milano\u2010Bicocca  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6372-2623","authenticated-orcid":false,"given":"Roberto","family":"Cairoli","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology ASST Grande Ospedale Metropolitano Niguarda  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8234-3474","authenticated-orcid":false,"given":"Alessandro","family":"Beghini","sequence":"additional","affiliation":[{"name":"Department of Health Sciences University of Milano  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408\u2010024\u201001143\u20102"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201062005\u20104"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2021.106727"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6929"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2009.01.009"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2011.11.003"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102013\u201005\u2010500850"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102013\u201008\u2010519843"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2008.02.004"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102004\u201010\u20104093"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15010024"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102011\u201010\u2010388611"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2011.02.001"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20080102"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2019.06.387"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201026394\u20106"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.435"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35808"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI42032"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102010\u201002\u2010270108"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.70119"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.3023"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102025\u20102016"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2023.283776"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2023.283917"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1918307117"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102025\u20107016"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81468"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201020\u20100184"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27547"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2011.06.023"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.139"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.21037\/sci.2017.01.06"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010016\u20100315\u20109"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010020\u20101002\u2010y"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010018\u20100566\u20108"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27411"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.197"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2019.100634"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/hem3.70069"}],"container-title":["Hematological Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hon.70254","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hon.70254","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hon.70254","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T10:13:44Z","timestamp":1792404824000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/hon.70254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":40,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/hon.70254"],"URL":"https:\/\/doi.org\/10.1002\/hon.70254","archive":["Portico"],"relation":{},"ISSN":["0278-0232","1099-1069"],"issn-type":[{"value":"0278-0232","type":"print"},{"value":"1099-1069","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-03-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70254"}}