{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:12:42Z","timestamp":1792102362641,"version":"4.4.0"},"reference-count":0,"publisher":"American Society of Hematology","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Trisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 cases. Our integrated genomic analyses identified 15 molecular subtypes of DS-ALL, with marked enrichment of CRLF2-r, IGH::IGF2BP1, and C\/EBP altered (C\/EBPalt) subtypes compared to 2257 non-DS-ALL cases. We observed abnormal activation of the CEBPD, CEBPA, and CEBPE genes in 10.5% of DS-ALL cases, via a variety of genomic mechanisms, including chromosomal rearrangements and noncoding mutations leading to enhancer hijacking. 42.3% of C\/EBP-activated DS-ALL also have concomitant FLT3 point mutation or indel, relative to 4.1% in other subtypes (P=7.2\u00d710-6). CEBPD overexpression enhanced the differentiation of mouse hematopoietic progenitor cells into pro-B cells in vitro, particularly in a DS genetic background. Notably, RAG-mediated somatic genomic abnormalities were common in DS-ALL, accounting for a median of 27.5% of structural alterations, compared to 7.7% in non-DS-ALL (P=2.1\u00d710-12). Unsupervised hierarchical clustering analyses of CRLF2-rearranged DS-ALL identified substantial heterogeneity within this group, with the BCR::ABL1-like subset linked to an inferior event-free survival (hazard ratio=5.27, P=9.3\u00d710-8), even after adjusting for known clinical risk factors (hazard ratio=4.32; P=0.0020). These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.<\/jats:p>","DOI":"10.1182\/blood.2023019765","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T20:11:40Z","timestamp":1680293500000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":23,"title":["Genomic landscape of Down syndrome-associated acute lymphoblastic leukemia"],"prefix":"10.1182","author":[{"given":"Zhenhua","family":"Li","sequence":"first","affiliation":[{"name":"St. Jude Children's Research Hospital, MEMPHIS, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ti-Cheng","family":"Chang","sequence":"additional","affiliation":[{"name":"St. Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2435-7739","authenticated-orcid":false,"given":"Jacob J","family":"Junco","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, Texas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1099-3478","authenticated-orcid":false,"given":"Meenakshi","family":"Devidas","sequence":"additional","affiliation":[{"name":"St Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8941-6691","authenticated-orcid":false,"given":"Yizhen","family":"Li","sequence":"additional","affiliation":[{"name":"St Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-5649","authenticated-orcid":false,"given":"Wenjian","family":"Yang","sequence":"additional","affiliation":[{"name":"St Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Huang","sequence":"additional","affiliation":[{"name":"St. Jude Children's Research Hospital, MEMPHIS, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale J","family":"Hedges","sequence":"additional","affiliation":[{"name":"St. Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongshan","family":"Cheng","sequence":"additional","affiliation":[{"name":"St Jude Children's Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Shago","sequence":"additional","affiliation":[{"name":"University of Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Carroll","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham, Birmingham, Alabama, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nyla A.","family":"Heerema","sequence":"additional","affiliation":[{"name":"The Ohio State University, Columbus, Ohio, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie M","family":"Gastier-Foster","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, Texas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7414-3969","authenticated-orcid":false,"given":"Brent L.","family":"Wood","sequence":"additional","affiliation":[{"name":"Childrens Hospital Los Angeles, Los Angeles, California, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Borowitz","sequence":"additional","affiliation":[{"name":"Johns Hopkins University, Baltimore, Maryland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2159-9310","authenticated-orcid":false,"given":"Lauren","family":"Sanclemente","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, Texas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Raetz","sequence":"additional","affiliation":[{"name":"New York University, New York, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P.","family":"Hunger","sequence":"additional","affiliation":[{"name":"Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Feingold","sequence":"additional","affiliation":[{"name":"University of Pittsburgh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracie C.","family":"Rosser","sequence":"additional","affiliation":[{"name":"Emory University, Atlanta, Georgia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie L.","family":"Sherman","sequence":"additional","affiliation":[{"name":"Emory University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mignon L.","family":"Loh","sequence":"additional","affiliation":[{"name":"Seattle Children's Hospital, the Ben Town Center for Childhood Cancer Research, University of Washington, Seattle, WA., Seattle, Washington, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1871-1850","authenticated-orcid":false,"given":"Charles G.","family":"Mullighan","sequence":"additional","affiliation":[{"name":"St Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1244-4429","authenticated-orcid":false,"given":"Jiyang","family":"Yu","sequence":"additional","affiliation":[{"name":"St. Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Wu","sequence":"additional","affiliation":[{"name":"St Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0978-5863","authenticated-orcid":false,"given":"Philip J","family":"Lupo","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, Texas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4081-8195","authenticated-orcid":false,"given":"Karen R","family":"Rabin","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine TX Children's Cancer Center, Houston, Texas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun J.","family":"Yang","sequence":"additional","affiliation":[{"name":"St. Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2023,3,31]]},"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2023019765\/2042122\/blood.2023019765.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2023019765\/2042122\/blood.2023019765.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T20:11:42Z","timestamp":1680293502000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2023019765\/495176\/Genomic-landscape-of-Down-syndrome-associated"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,31]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2023019765","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,31]]},"article-number":"blood.2023019765"}}