{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:21:17Z","timestamp":1787736077729,"version":"build-2784847793"},"reference-count":32,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Oncol.","Current Oncology"],"abstract":"<jats:p>The benefits of lenalidomide, which leverages TP53-dependent apoptosis and promotion of megakaryocytic differentiation, in lower-risk MDS (LR-MDS) with del(5q) are well-established and drive its frequent use in clinical practice. In parallel, advances in molecular testing have elucidated the clear impact of TP53 mutations on response to therapies and prognosis, with diversity in the latter informed by variant allele frequency (VAF) and\/or predicted allelic state. In this review, we discuss the converging pre-clinical and clinical evidence that implicates TP53 mutations not only as a driver of lenalidomide resistance in del(5q) LR-MDS, but as a source of selective clonal advantage under lenalidomide exposure. Lenalidomide-induced CK1\u03b1 degradation triggers TP53-mediated apoptosis in wild-type clones, inadvertently favoring the survival and expansion of TP53-mutated cells. Clinically, this dynamic has been demonstrated across multiple studies, with rising TP53 variant allele frequency and clonal evolution observed following treatment. These findings underscore the importance of baseline molecular assessment in patients with MDS and, in select cases, serial monitoring during therapy. Investigational approaches for del(5q) LR-MDS with the TP53 mutation include GATA2-directed strategies aimed at restoring lenalidomide sensitivity, as well as immune-based therapies targeting the tumor microenvironment characteristic of TP53-mutated disease.<\/jats:p>","DOI":"10.3390\/curroncol33090506","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:11:15Z","timestamp":1787731875000},"page":"506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lenalidomide Exposure and TP53-Mutated Myelodysplastic Syndromes\/Neoplasms"],"prefix":"10.3390","volume":"33","author":[{"given":"Bahga","family":"Katamesh","sequence":"first","affiliation":[{"name":"Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory M.","family":"Shallis","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1016\/S0140-6736(13)61901-7","article-title":"Myelodysplastic syndromes","volume":"383","author":"Itzykson","year":"2014","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1182\/blood.2023023727","article-title":"Molecular taxonomy of myelodysplastic syndromes and its clinical implications","volume":"144","author":"Bernard","year":"2024","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1182\/blood.2025028619","article-title":"A precision medicine approach to the myelodysplastic syndrome with isolated deletion 5q, 50 years after its discovery","volume":"146","author":"Roncador","year":"2025","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1182\/blood.2023020078","article-title":"Diagnosis and classification of myelodysplastic syndromes","volume":"142","author":"Hasserjian","year":"2023","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1182\/blood-2011-01-330126","article-title":"A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-\/Intermediate-1-risk myelodysplastic syndromes with del5q","volume":"118","author":"Fenaux","year":"2011","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1038\/leu.2013.305","article-title":"Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS","volume":"28","author":"List","year":"2014","journal-title":"Leukemia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e659","DOI":"10.1016\/S2352-3026(24)00142-X","article-title":"Low dose lenalidomide versus placebo in non-transfusion dependent patients with low risk, del(5q) myelodysplastic syndromes (SintraREV): A randomised, double-blind, phase 3 trial","volume":"11","author":"Xicoy","year":"2024","journal-title":"Lancet Haematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3324\/haematol.2016.152025","article-title":"Progression in patients with low- and intermediate-1-risk del(5q) myelodysplastic syndromes is predicted by a limited subset of mutations","volume":"102","author":"Scharenberg","year":"2017","journal-title":"Haematologica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.1016\/j.clml.2024.10.007","article-title":"Lenalidomide in Transfusion-Dependent IPSS Low- or Intermediate-1-Risk Myelodysplastic Syndromes and Isolated Del(5q): Results of a European Postauthorization Safety Surveillance Study","volume":"25","author":"Poloni","year":"2025","journal-title":"Clin. 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