{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:32:16Z","timestamp":1792805536146,"version":"4.5.0"},"reference-count":60,"publisher":"American Society of Hematology","issue":"25","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,6,20]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory\/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05\/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n\u00a0= 7) or TP53 mutations (n\u00a0= 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P\u00a0&amp;lt; .001; 25.0% vs 89.5%; P\u00a0&amp;lt; .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023022247","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T20:54:31Z","timestamp":1711054471000},"page":"2627-2643","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":31,"title":["Landscape of driver mutations and their clinical effects on Down syndrome\u2013related myeloid neoplasms"],"prefix":"10.1182","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1456-6887","authenticated-orcid":false,"given":"Tomohiko","family":"Sato","sequence":"first","affiliation":[{"name":"1Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4612-2778","authenticated-orcid":false,"given":"Kenichi","family":"Yoshida","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan"},{"name":"3Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0061-9781","authenticated-orcid":false,"given":"Tsutomu","family":"Toki","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4384-4871","authenticated-orcid":false,"given":"Rika","family":"Kanezaki","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1294-8635","authenticated-orcid":false,"given":"Kiminori","family":"Terui","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6984-7187","authenticated-orcid":false,"given":"Ryunosuke","family":"Saiki","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masami","family":"Ojima","sequence":"additional","affiliation":[{"name":"4Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yotaro","family":"Ochi","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6740-5817","authenticated-orcid":false,"given":"Seiya","family":"Mizuno","sequence":"additional","affiliation":[{"name":"5Laboratory Animal Resource Center and Trans-border Medical Research Center, University of Tsukuba, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0212-0909","authenticated-orcid":false,"given":"Masaharu","family":"Yoshihara","sequence":"additional","affiliation":[{"name":"5Laboratory Animal Resource Center and Trans-border Medical Research Center, University of Tsukuba, Tsukuba, Japan"},{"name":"6School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6630-7847","authenticated-orcid":false,"given":"Tamayo","family":"Uechi","sequence":"additional","affiliation":[{"name":"7Department of Anatomy, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5178-0658","authenticated-orcid":false,"given":"Naoya","family":"Kenmochi","sequence":"additional","affiliation":[{"name":"7Department of Anatomy, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6817-5235","authenticated-orcid":false,"given":"Shiro","family":"Tanaka","sequence":"additional","affiliation":[{"name":"8Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4104-6833","authenticated-orcid":false,"given":"Jun","family":"Matsubayashi","sequence":"additional","affiliation":[{"name":"9Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8046-9276","authenticated-orcid":false,"given":"Kenta","family":"Kisai","sequence":"additional","affiliation":[{"name":"8Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8214-1787","authenticated-orcid":false,"given":"Ko","family":"Kudo","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, 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