{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:54:50Z","timestamp":1790963690039,"version":"4.1.0"},"reference-count":0,"publisher":"American Society of Hematology","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>TP53 mutations represent one of the strongest adverse prognostic factors in myelodysplastic neoplasms (MDS). While multi-hit TP53 (TP53multiHit) alterations uniformly lead to very poor outcomes, the prognostic relevance of monoallelic TP53 (TP53mono) mutations remains controversial. TP53 variants can cause dominant-negative, loss-of-function, or gain-of-function effects. We hypothesized that functional heterogeneity among TP53 variants contributes to the variable clinical behavior observed in TP53mono-mutated MDS. Therefore, we analyzed pretreatment samples from 4,505 patients with MDS from two independent cohorts (IWG: n=3,173; J-MDS: n=1,332), including 271 patients with TP53mono and 499 with TP53multiHit. Functional annotation of TP53 variants was performed using a previously published phenotype score (PS) derived from saturation mutagenesis screens, capturing dominant-negative and loss-of-function effects. Median leukemia-free survival (LFS) differed significantly by TP53 allelic state (TP53 wild-type (TP53wt) 37.2 months; TP53mono 19.2 months; TP53multiHit 7.8 months; p&amp;lt;0.001). Within the TP53mono subgroup, functional annotation identified marked heterogeneity. Patients with high PS (\u22657) showed a significantly inferior median LFS compared with those with low PS (12.6 vs. 43.3 months; p&amp;lt;0.001), particularly for IPSS-R and IPSS-M low-risk cases. Combining PS and variant allele frequency (VAF) further improved risk stratification. TP53mono patients with PS \u22657 and VAF \u226522% had a median LFS comparable to TP53multiHit cases (9.2 vs. 7.8 months, p=0.3), whereas those with PS &amp;lt;7 and VAF &amp;lt;22% exhibited a median LFS similar to TP53wt cases (44.7 vs. 37.2 months, p=0.8). Overall, functional annotation of TP53 variants refines prognostication in TP53mono-mutated MDS and may enhance individualized risk assessment.<\/jats:p>","DOI":"10.1182\/blood.2026034224","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:58:34Z","timestamp":1790881114000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["Functional Classification of Monoallelic TP53 Mutations Refines Prognostic Stratification in Myelodysplastic Neoplasms"],"prefix":"10.1182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3531-534X","authenticated-orcid":false,"given":"Alexander","family":"Streuer","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yotaro","family":"Ochi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2432-8898","authenticated-orcid":false,"given":"Stephan","family":"Hutter","sequence":"additional","affiliation":[{"name":"MLL Munich Leukemia Laboratory, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Riabov","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6526-0992","authenticated-orcid":false,"given":"Yasuhito","family":"Nannya","sequence":"additional","affiliation":[{"name":"Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4524-037X","authenticated-orcid":false,"given":"Laurenz","family":"Steiner","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1211-0843","authenticated-orcid":false,"given":"Mohammed","family":"Abba","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Metzgeroth","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Altrock","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0968-1546","authenticated-orcid":false,"given":"Felicitas","family":"Rapp","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edin","family":"Hepg\u00fcl\u00fcm","sequence":"additional","affiliation":[{"name":"Heidelberg University, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9937-0957","authenticated-orcid":false,"given":"Steffen","family":"Boettcher","sequence":"additional","affiliation":[{"name":"University of Zurich and University Hospital Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Haferlach","sequence":"additional","affiliation":[{"name":"MLL Munich Leukemia Laboratory, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7130-7921","authenticated-orcid":false,"given":"Daniel","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolf-Karsten","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7778-5374","authenticated-orcid":false,"given":"Seishi","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3455-9606","authenticated-orcid":false,"given":"Nanni","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2026,10,1]]},"container-title":["Blood Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026034224\/2593718\/blood.2026034224.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026034224\/2593718\/blood.2026034224.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:30:00Z","timestamp":1790962200000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2026034224\/571347\/Functional-Classification-of-Monoallelic-TP53"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2026034224","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"blood.2026034224"}}