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This study aimed to evaluate HDM201, a second-generation MDM2-p53 binding antagonist, as a novel therapeutic strategy for CLL, with a focus on its effectiveness across different TP53 genetic contexts. Methods: We utilized a panel of B cell leukemia-derived cell lines with varying TP53 statuses, including TP53-knockout (KO) derivatives of the human B cell line Nalm-6, and assessed the impact of HDM201 on primary CLL samples with both TP53 wild-type and mutant backgrounds. Results: Our results revealed that TP53 wild-type and heterozygous TP53-KO Nalm-6 cells were sensitive to HDM201, whereas homozygous TP53-KO cells and B cells with TP53 mutations exhibited significant resistance. Resistance was also noted in primary CLL samples with TP53 mutations. HDM201 effectively stabilized p53 and induced apoptosis in TP53 wild-type cells but had limited efficacy in TP53 mutant cells. Conclusions: These findings indicate that HDM201 holds promise as an additional targeted therapy option for wild-type TP53 CLL. The results underline the importance of TP53 status in predicting treatment efficacy and highlight the potential of HDM201 as a valuable addition to explore in CLL therapy. Future research should focus on identifying additional biomarkers of response and exploring the optimal way to include HDM201 in combination therapies to improve treatment outcomes in CLL.<\/jats:p>","DOI":"10.3390\/cancers17020274","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T04:55:19Z","timestamp":1737003319000},"page":"274","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting the MDM2-p53 Interaction with Siremadlin: A Promising Therapeutic Strategy for Treating TP53 Wild-Type Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9400-0938","authenticated-orcid":false,"given":"Erhan","family":"Aptullahoglu","sequence":"first","affiliation":[{"name":"Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Department of Molecular Biology and Genetics, Faculty of Science, Bilecik \u015eeyh Edebali University, 11100 Bilecik, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Howladar","sequence":"additional","affiliation":[{"name":"Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan P.","family":"Wallis","sequence":"additional","affiliation":[{"name":"Department of Haematology, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Marr","sequence":"additional","affiliation":[{"name":"Department of Haematology, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Haematology, City Hospitals Sunderland NHS Trust, Sunderland SR4 7TP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Irving","sequence":"additional","affiliation":[{"name":"Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4762-094X","authenticated-orcid":false,"given":"Elaine","family":"Willmore","sequence":"additional","affiliation":[{"name":"Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1878-8583","authenticated-orcid":false,"given":"John","family":"Lunec","sequence":"additional","affiliation":[{"name":"Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1056\/NEJMra041720","article-title":"Chronic lymphocytic leukemia","volume":"352","author":"Chiorazzi","year":"2005","journal-title":"N. 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