{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:32:06Z","timestamp":1785843126921,"version":"3.56.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T00:00:00Z","timestamp":1575244800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T00:00:00Z","timestamp":1575244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recent advances in molecular diagnostics have shown that lesions affecting both copies of the gene for tumor suppressor protein 53 (<jats:italic>TP53<\/jats:italic>) count among the most powerful predictors for high-risk disease in multiple myeloma (MM). However, the functional relevance and potential therapeutic implications of single hits to <jats:italic>TP53<\/jats:italic> remain less well understood. Here, we have for the first time approximated the different constellations of mono- and bi-allelic <jats:italic>TP53<\/jats:italic> lesions observed in MM patients within the frame of a single MM cell line model and assessed their potential to disrupt p53 system functionality and to impart drug resistance. Both types of common first hit: point mutation with expression of mutant p53 protein or complete loss of contribution from one of two wildtype alleles strongly impaired p53 system functionality and increased resistance to melphalan. Second hits abolished remaining p53 activity and increased resistance to genotoxic drugs even further. These results fit well with the clinical drive to <jats:italic>TP53<\/jats:italic> single- and double-hit disease in MM patients, provide a rationale for the most commonly observed double-hit constellation (del17p+ <jats:italic>TP53<\/jats:italic> point mutation), and underscore the potential increases in MM cell malignancy associated with any type of initial <jats:italic>TP53<\/jats:italic> lesion.<\/jats:p>","DOI":"10.1038\/s41598-019-54407-4","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T11:37:14Z","timestamp":1575286634000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Assessment of TP53 lesions for p53 system functionality and drug resistance in multiple myeloma using an isogenic cell line model"],"prefix":"10.1038","volume":"9","author":[{"given":"Umair","family":"Munawar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Barrio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2005-3949","authenticated-orcid":false,"given":"Harald","family":"Wajant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Siegmund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf C.","family":"Bargou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7011-0286","authenticated-orcid":false,"given":"K. Martin","family":"Kort\u00fcm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5544-3018","authenticated-orcid":false,"given":"Thorsten","family":"St\u00fchmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,2]]},"reference":[{"key":"54407_CR1","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1056\/NEJMra1011442","volume":"364","author":"A Palumbo","year":"2011","unstructured":"Palumbo, A. & Anderson, K. Multiple myeloma. N. Engl. J. Med. 364, 1046\u20131060 (2011).","journal-title":"N. Engl. J. Med."},{"key":"54407_CR2","doi-asserted-by":"publisher","first-page":"5428","DOI":"10.1158\/1078-0432.CCR-16-0866","volume":"22","author":"O Landgren","year":"2017","unstructured":"Landgren, O. & Rajkumar, S. V. New developments in diagnosis, prognosis, and assessment of response in multiple myeloma. Clin. Cancer Res. 22, 5428\u20135433 (2017).","journal-title":"Clin. Cancer Res."},{"key":"54407_CR3","doi-asserted-by":"publisher","first-page":"2443","DOI":"10.1038\/leu.2017.138","volume":"31","author":"SK Kumar","year":"2017","unstructured":"Kumar, S. K. et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia 31, 2443\u20132448 (2017).","journal-title":"Leukemia"},{"key":"54407_CR4","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/s41375-018-0196-8","volume":"33","author":"BA Walker","year":"2019","unstructured":"Walker, B. A. et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia 33, 159\u2013170 (2019).","journal-title":"Leukemia"},{"key":"54407_CR5","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.1200\/JCO.2015.61.2267","volume":"33","author":"A Palumbo","year":"2015","unstructured":"Palumbo, A. et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J. Clin. Oncol. 33, 2863\u20132869 (2015).","journal-title":"J. Clin. Oncol."},{"key":"54407_CR6","doi-asserted-by":"publisher","first-page":"2604","DOI":"10.1038\/s41375-018-0037-9","volume":"32","author":"N Bolli","year":"2018","unstructured":"Bolli, N. et al. Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia 32, 2604\u20132616 (2018).","journal-title":"Leukemia"},{"key":"54407_CR7","doi-asserted-by":"publisher","first-page":"E473","DOI":"10.1002\/ajh.24533","volume":"91","author":"M Merz","year":"2016","unstructured":"Merz, M. et al. Baseline characteristics, chromosomal alterations, and treatment affecting prognosis of deletion 17p in newly diagnosed myeloma. Am. J. Hematol. 91, E473\u2013E477 (2016).","journal-title":"Am. J. Hematol."},{"key":"54407_CR8","doi-asserted-by":"crossref","unstructured":"Perrot, A., Corre, J. & Avet-Loiseau, H. Risk stratification and targets in multiple myeloma: from genomics to bedside. ASCO Educational Book, 675\u2013680 (2018).","DOI":"10.1200\/EDBK_200879"},{"key":"54407_CR9","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1038\/leu.2014.102","volume":"28","author":"PJ Teoh","year":"2014","unstructured":"Teoh, P. J. et al. p53 haploinsufficiency and functional abnormalities in multiple myeloma. Leukemia 28, 2066\u20132074 (2014).","journal-title":"Leukemia"},{"key":"54407_CR10","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.3324\/haematol.2010.023697","volume":"95","author":"L Lod\u00e9","year":"2010","unstructured":"Lod\u00e9, L. et al. Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma. Haematologica 95, 1973\u20131976 (2010).","journal-title":"Haematologica"},{"key":"54407_CR11","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1111\/bjh.13171","volume":"168","author":"KM Kort\u00fcm","year":"2015","unstructured":"Kort\u00fcm, K. M. et al. Targeted sequencing using a 47 gene multiple myeloma panel (M3P) in \u221217p high risk disease. Br. J. Haematol. 168, 507\u2013510 (2015).","journal-title":"Br. J. Haematol."},{"key":"54407_CR12","doi-asserted-by":"publisher","first-page":"21353","DOI":"10.18632\/oncotarget.7241","volume":"7","author":"M Lionetti","year":"2016","unstructured":"Lionetti, M. et al. Molecular spectrum of TP53 mutations in plasma cell dyscrasias by next generation sequencing: an Italian cohort study and overview of the literature. 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