{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:47:26Z","timestamp":1792784846666,"version":"4.5.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70113602"],"award-info":[{"award-number":["70113602"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hector Stiftung M2204"},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["413501650"],"award-info":[{"award-number":["413501650"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mildred-Scheel Nachwuchszentrum"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Treatment of high-risk Myelodysplastic Neoplasms (hr-MDS) and (secondary) Acute Myeloid Leukemia (AML) remains a clinical challenge. The combination of azacitidine and venetoclax (aza\/ven) may improve treatment outcomes, but still fails in a significant fraction of patients. We established a single-center collection of longitudinal samples from patients with MDS and AML\/sAML and performed comprehensive genetic, proteomic and functional apoptosis profiling to identify biomarkers and targetable escape mechanisms to aza\/ven. Baseline genetic characterization (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200955) identified high-risk genetic alterations, while longitudinal analyses (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009268, mean 8.7 [3\u201320] timepoints) revealed distinct genetic profiles of clonal evolution. Functional BH3-profiling at treatment initiation identified heterogeneous dependencies on BCL-2 family members. Notably, high BCL-2 dependence correlated with genetic response to aza\/ven and improved overall survival, whereas increased BCL-xL dependence was associated with resistance. We further identified patterns of acquired resistance, with loss of apoptotic priming and shifts in anti-apoptotic dependencies contributing to treatment failure. BH3 profiling revealed functional shifts toward MCL-1 and\/or BCL-xL in individual cases, suggesting potential therapeutic targets to overcome resistance. In vitro, BCL-xL inhibition effectively counteracted resistance in increased BCL-xL dependence cases. In summary, we characterized treatment-associated clonal evolution in MDS and AML, providing insights into clinical response, disease progression and potential individualized therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02756-7","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T17:02:20Z","timestamp":1758301340000},"page":"3026-3036","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Clonal evolution and apoptosis resistance in myelodysplastic neoplasms and acute myeloid leukemia under treatment: insights from integrative longitudinal profiling"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6317-0216","authenticated-orcid":false,"given":"Paolo","family":"Mazzeo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Mae","family":"Penir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgenii","family":"Shumilov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"H\u00e4upl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Markus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katayoon","family":"Shirneshan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Rittscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elzbieta","family":"Brzuszkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1418-2725","authenticated-orcid":false,"given":"Enver","family":"Aydilek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4436-5493","authenticated-orcid":false,"given":"Hannes","family":"Treiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Oellerich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7566-5985","authenticated-orcid":false,"given":"Christina","family":"Ganster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Detlef","family":"Haase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2018-5685","authenticated-orcid":false,"given":"Raphael","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,19]]},"reference":[{"key":"2756_CR1","doi-asserted-by":"crossref","first-page":"3616","DOI":"10.1182\/blood-2013-08-518886","volume":"122","author":"E Papaemmanuil","year":"2013","unstructured":"Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616\u201327.","journal-title":"Blood"},{"key":"2756_CR2","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1182\/blood.V86.1.268.bloodjournal861268","volume":"86","author":"A Raza","year":"1995","unstructured":"Raza A, Gezer S, Mundle S, Gao XZ, Alvi S, Borok R, et al. Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood. 1995;86:268\u201376.","journal-title":"Blood"},{"key":"2756_CR3","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1038\/leu.2015.69","volume":"29","author":"I Ga\u00f1\u00e1n-G\u00f3mez","year":"2015","unstructured":"Ga\u00f1\u00e1n-G\u00f3mez I, Wei Y, Starczynowski DT, Colla S, Yang H, Cabrero-Calvo M, et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia. 2015;29:1458\u201369.","journal-title":"Leukemia"},{"key":"2756_CR4","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1182\/blood.V73.1.248.248","volume":"73","author":"J Janssen","year":"1989","unstructured":"Janssen J, Buschle M, Layton M, Drexler H, Lyons J, van den Berghe H, et al. Clonal analysis of myelodysplastic syndromes: evidence of multipotent stem cell origin. Blood. 1989;73:248\u201354.","journal-title":"Blood"},{"key":"2756_CR5","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1056\/NEJMra0902908","volume":"19","author":"A Tefferi","year":"2009","unstructured":"Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med. 2009;19:1872\u201385.","journal-title":"N Engl J Med"},{"key":"2756_CR6","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1182\/blood-2008-10-182782","volume":"113","author":"OK Weinberg","year":"2009","unstructured":"Weinberg OK, Seetharam M, Ren L, Seo K, Ma L, Merker JD, et al. Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system. Blood. 2009;113:1906\u20138.","journal-title":"Blood"},{"key":"2756_CR7","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1182\/blood-2018-10-844696","volume":"133","author":"U Platzbecker","year":"2019","unstructured":"Platzbecker U. Treatment of MDS. Blood. 2019;133:1096\u2013107.","journal-title":"Blood"},{"key":"2756_CR8","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1200\/JCO.2011.35.8135","volume":"29","author":"T Pr\u00e9bet","year":"2011","unstructured":"Pr\u00e9bet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine Treatment failure. Journal Clin Oncol. 2011;29:3322\u20137.","journal-title":"Journal Clin Oncol"},{"key":"2756_CR9","doi-asserted-by":"crossref","unstructured":"Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. 2016;24:3895\u2013903.","DOI":"10.1200\/JCO.2005.05.4346"},{"key":"2756_CR10","doi-asserted-by":"crossref","unstructured":"Garcia JS, Jain N, Godley LA. An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes. Onco Targets Ther. 2010;3:1\u201313.","DOI":"10.2147\/OTT.S7222"},{"key":"2756_CR11","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S1470-2045(09)70003-8","volume":"10","author":"P Fenaux","year":"2009","unstructured":"Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223\u201332.","journal-title":"Lancet Oncol"},{"key":"2756_CR12","doi-asserted-by":"crossref","unstructured":"Bernard E, Tuechler H, Greenberg PL, Hasserjian RP, Arango Ossa JE, Nannya Y, et al. Molecular international prognostic scoring system for myelodysplastic syndromes. NEJM Evid. 2022;1:EVIDoa2200008.","DOI":"10.1056\/EVIDoa2200008"},{"key":"2756_CR13","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1182\/blood.2022016867","volume":"140","author":"H D\u00f6hner","year":"2022","unstructured":"D\u00f6hner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140:1345\u201377.","journal-title":"Blood"},{"key":"2756_CR14","doi-asserted-by":"crossref","unstructured":"Schanz J, Cevik N, Fonatsch C, Braulke F, Shirneshan K, Bacher U, et al. Detailed analysis of clonal evolution and cytogenetic evolution patterns in patients with myelodysplastic syndromes (MDS) and related myeloid disorders. Blood Cancer J. 2018;8:28.","DOI":"10.1038\/s41408-018-0061-z"},{"key":"2756_CR15","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/ng.3742","volume":"49","author":"H Makishima","year":"2017","unstructured":"Makishima H, Yoshizato T, Yoshida K, Sekeres MA, Radivoyevitch T, Suzuki H, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet. 2017;49:204\u201312.","journal-title":"Nat Genet"},{"key":"2756_CR16","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1182\/blood.2019000942","volume":"136","author":"AJ Menssen","year":"2020","unstructured":"Menssen AJ, Walter MJ. Genetics of progression from MDS to secondary leukemia. Blood. 2020;136:50\u201360.","journal-title":"Blood"},{"key":"2756_CR17","doi-asserted-by":"crossref","DOI":"10.1002\/hem3.70014","volume":"8","author":"P Mazzeo","year":"2024","unstructured":"Mazzeo P, Ganster C, Wiedenh\u00f6ft J, Shirneshan K, Rittscher K, Brzuszkiewicz EB, et al. Comprehensive sequential genetic analysis delineating frequency, patterns, and prognostic impact of genomic dynamics in a real-world cohort of patients with lower-risk MDS. Hemasphere. 2024;8:e70014.","journal-title":"Hemasphere"},{"key":"2756_CR18","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/cdd.2017.186","volume":"25","author":"J Kale","year":"2018","unstructured":"Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ. 2018;25:65\u201380.","journal-title":"Cell Death Differ"},{"key":"2756_CR19","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1002\/ijc.34377","volume":"152","author":"S Blum","year":"2023","unstructured":"Blum S, Tsilimidos G, Bresser H, L\u00fcbbert M. Role of Bcl-2 inhibition in myelodysplastic syndromes. Int J Cancer. 2023;152:1526\u201335.","journal-title":"Int J Cancer"},{"key":"2756_CR20","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1182\/blood-2018-03-828269","volume":"132","author":"M Konopleva","year":"2018","unstructured":"Konopleva M, Letai A. BCL-2 inhibition in AML: an unexpected bonus?. Blood. 2018;132:1007\u201312.","journal-title":"Blood"},{"key":"2756_CR21","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJMoa2012971","volume":"383","author":"CD DiNardo","year":"2020","unstructured":"DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383:617\u201329.","journal-title":"N Engl J Med"},{"key":"2756_CR22","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40164-019-0133-1","volume":"8","author":"S Jilg","year":"2019","unstructured":"Jilg S, Hauch RT, Kauschinger J, Buschhorn L, Odinius TO, Dill V, et al. Venetoclax with azacitidine targets refractory MDS but spares healthy hematopoiesis at tailored dose. Exp Hematol Oncol. 2019;8:6\u201310.","journal-title":"Exp Hematol Oncol"},{"key":"2756_CR23","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1080\/16078454.2020.1843752","volume":"25","author":"B Liu","year":"2020","unstructured":"Liu B, Guo Y, Deng L, Qiao Y, Jian J. The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis. Hematology. 2020;25:414\u201323.","journal-title":"Hematology"},{"key":"2756_CR24","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1126\/scitranslmed.aax2863","volume":"11","author":"D Sharon","year":"2019","unstructured":"Sharon D, Cathelin S, Mirali S, Di Trani JM, Yanofsky DJ, Keon KA, et al. Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response. Sci Transl Med. 2019;11:2863.","journal-title":"Sci Transl Med"},{"key":"2756_CR25","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1038\/s41591-018-0233-1","volume":"24","author":"DA Pollyea","year":"2018","unstructured":"Pollyea DA, Stevens BM, Jones CL, Winters A, Pei S, Minhajuddin M, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nature Med. 2018;24:1859\u201366.","journal-title":"Nature Med"},{"key":"2756_CR26","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.ccell.2020.10.010","volume":"38","author":"S Bhatt","year":"2020","unstructured":"Bhatt S, Pioso MS, Olesinski EA, Yilma B, Ryan JA, Mashaka T, et al. Reduced mitochondrial apoptotic priming drives resistance to BH3 mimetics in acute myeloid leukemia. Cancer Cell. 2020;38:872\u201390.e6.","journal-title":"Cancer Cell"},{"key":"2756_CR27","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/nmeth.2834","volume":"11","author":"NA Kulak","year":"2014","unstructured":"Kulak NA, Pichler G, Paron I, Nagaraj N, Mann M. Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells. Nat Methods. 2014;11:319\u201324.","journal-title":"Nat Methods"},{"key":"2756_CR28","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1158\/2159-8290.CD-18-1119","volume":"9","author":"P Blombery","year":"2019","unstructured":"Blombery P, Anderson MA, Gong JN, Thijssen R, Birkinshaw RW, Thompson ER, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019;9:342\u201353.","journal-title":"Cancer Discov"},{"key":"2756_CR29","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1158\/2159-8290.CD-14-0353","volume":"4","author":"TN Chonghaile","year":"2014","unstructured":"Chonghaile TN, Chonghaile T, Roderick JE, Glenfield C, Ryan J, Sallan SE, et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov. 2014;4:1074\u201387.","journal-title":"Cancer Discov"},{"key":"2756_CR30","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1515\/hsz-2016-0107","volume":"397","author":"J Ryan","year":"2016","unstructured":"Ryan J, Montero J, Rocco J, Letai A. iBH3: simple, fixable BH3 profiling to determine apoptotic priming in primary tissue by flow cytometry. Biol Chem. 2016;397:671\u20138.","journal-title":"Biol Chem"},{"key":"2756_CR31","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1182\/blood-2023-187102","volume":"142","author":"G Garcia-Manero","year":"2023","unstructured":"Garcia-Manero G, Odenike O, Fleming S, Roboz GJ, Jacoby M, Cunningham I, et al. Combination of venetoclax and azacitidine in patients with treatment-naive, high-risk myelodysplastic syndromes with responses leading to stem cell transplantation. Blood. 2023;142:1868.","journal-title":"Blood"},{"key":"2756_CR32","doi-asserted-by":"crossref","first-page":"e756","DOI":"10.1016\/S2352-3026(22)00216-2","volume":"9","author":"A Bazinet","year":"2022","unstructured":"Bazinet A, Darbaniyan F, Jabbour E, Montalban-Bravo G, Ohanian M, Chien K, et al. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1\u20132 study. Lancet Haematol. 2022;9:e756\u201365.","journal-title":"Lancet Haematol"},{"key":"2756_CR33","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/ajh.27246","volume":"99","author":"KW Pratz","year":"2024","unstructured":"Pratz KW, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, D\u00f6hner H, et al. Long-term follow-up of <scp>VIALE-A<\/scp>: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol. 2024;99:615\u201324.","journal-title":"Am J Hematol"},{"key":"2756_CR34","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1158\/1078-0432.CCR-19-1900","volume":"26","author":"S Jin","year":"2020","unstructured":"Jin S, Cojocari D, Purkal JJ, Popovic R, Talaty NN, Xiao Y, et al. 5-azacitidine induces NOXA to prime AML cells for venetoclax-mediated apoptosis. Clinical Cancer Res. 2020;26:3371\u201383.","journal-title":"Clinical Cancer Res"},{"key":"2756_CR35","doi-asserted-by":"crossref","first-page":"226","DOI":"10.3109\/10428194.2014.910657","volume":"56","author":"JM Bogenberger","year":"2015","unstructured":"Bogenberger JM, Delman D, Hansen N, Valdez R, Fauble V, Mesa RA, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015;56:226.","journal-title":"Leuk Lymphoma"},{"key":"2756_CR36","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1182\/blood.2024024944","volume":"144","author":"H D\u00f6hner","year":"2024","unstructured":"D\u00f6hner H, Pratz KW, DiNardo CD, Wei AH, Jonas BA, Pullarkat VA, et al. Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine. Blood. 2024;144:2211\u201322.","journal-title":"Blood"},{"key":"2756_CR37","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.2147\/OTT.S89275","volume":"8","author":"J Zhang","year":"2015","unstructured":"Zhang J, Wang S, Wang L, Wang R, Chen S, Pan B, et al. Prognostic value of Bcl-2 expression in patients with non-small-cell lung cancer: a meta-analysis and systemic review. Onco Targets Ther. 2015;8:3361\u20139.","journal-title":"Onco Targets Ther"},{"key":"2756_CR38","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s10495-022-01780-7","volume":"28","author":"D Kaloni","year":"2022","unstructured":"Kaloni D, Diepstraten ST, Strasser A, Kelly GL. BCL-2 protein family: attractive targets for cancer therapy. Apoptosis. 2022;28:20\u201338.","journal-title":"Apoptosis"},{"key":"2756_CR39","volume":"12","author":"S Qian","year":"2022","unstructured":"Qian S, Wei Z, Yang W, Huang J, Yang Y, Wang J. The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front Oncol. 2022;12:985363.","journal-title":"Front Oncol"},{"key":"2756_CR40","first-page":"1","volume":"14","author":"JD Zhou","year":"2019","unstructured":"Zhou JD, Zhang TJ, Xu ZJ, Gu Y, Ma JC, Li XX, et al. BCL2 overexpression: Clinical implication and biological insights in acute myeloid leukemia. Diagn Pathol. 2019;14:1\u201310.","journal-title":"Diagn Pathol"},{"key":"2756_CR41","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.stem.2012.12.013","volume":"12","author":"ED Lagadinou","year":"2013","unstructured":"Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329\u201341.","journal-title":"Cell Stem Cell"},{"key":"2756_CR42","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1158\/2159-8290.CD-16-0313","volume":"6","author":"M Konopleva","year":"2016","unstructured":"Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106\u201317.","journal-title":"Cancer Discov"},{"key":"2756_CR43","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1182\/blood.2024024968","volume":"145","author":"S Kyt\u00f6l\u00e4","year":"2025","unstructured":"Kyt\u00f6l\u00e4 S, V\u00e4nttinen I, Ruokoranta T, Partanen A, Holopainen A, Saad J, et al. Ex vivo venetoclax sensitivity predicts clinical response in acute myeloid leukemia in the prospective VenEx trial. Blood. 2025;145:409\u201321.","journal-title":"Blood"},{"key":"2756_CR44","first-page":"309","volume":"123","author":"O Warburg","year":"1956","unstructured":"Warburg O. On the origin of cancer cells. Science (1979). 1956;123:309\u201314.","journal-title":"Science (1979)"},{"key":"2756_CR45","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41580-018-0089-8","volume":"20","author":"R Singh","year":"2019","unstructured":"Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nature Rev Mol Cell Biol. 2019;20:175\u201393.","journal-title":"Nature Rev Mol Cell Biol"},{"key":"2756_CR46","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/nrc776","volume":"2","author":"FH Igney","year":"2002","unstructured":"Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 2002;2:277\u201388.","journal-title":"Nat Rev Cancer"},{"key":"2756_CR47","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1038\/s41591-019-0668-z","volume":"25","author":"S Khan","year":"2019","unstructured":"Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938\u201347.","journal-title":"Nat Med"},{"key":"2756_CR48","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1158\/1078-0432.CCR-23-1525","volume":"30","author":"NJ Lakhani","year":"2024","unstructured":"Lakhani NJ, Rasco D, Wang H, Men L, Liang E, Fu T, et al. First-in-human study with preclinical data of BCL-2\/ BCL-xL inhibitor pelcitoclax in locally advanced or metastatic solid tumors. Clinical Cancer Res. 2024;30:506\u201321.","journal-title":"Clinical Cancer Res"},{"key":"2756_CR49","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.1200\/JCO.2023.41.16_suppl.3027","volume":"41","author":"BA Carneiro","year":"2023","unstructured":"Carneiro BA, Perets R, Dowlati A, LoRusso P, Yonemori K, He L, et al. Mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed\/refractory solid tumors: dose expansion results. Journal Clin Oncol. 2023;41:3027\u20133027.","journal-title":"Journal Clin Oncol"},{"key":"2756_CR50","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1200\/JCO.2021.39.15_suppl.3015","volume":"39","author":"AW Tolcher","year":"2021","unstructured":"Tolcher AW, Carneiro BA, Dowlati A, Razak ARA, Chae YK, Villella JA, et al. A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed\/refractory solid tumors: Dose escalation results. J Clin Oncol. 2021;39:3015.","journal-title":"J Clin Oncol"},{"key":"2756_CR51","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.pharmthera.2019.02.007","volume":"198","author":"AW Hird","year":"2019","unstructured":"Hird AW, Tron AE. Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharmacol Ther. 2019;198:59\u201367.","journal-title":"Pharmacol Ther"},{"key":"2756_CR52","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1080\/13543776.2019.1672661","volume":"29","author":"S Fletcher","year":"2019","unstructured":"Fletcher S. MCL-1 inhibitors \u2013 where are we now (2019)?. Expert Opin Ther Pat. 2019;29:909\u201319.","journal-title":"Expert Opin Ther Pat"},{"key":"2756_CR53","doi-asserted-by":"crossref","first-page":"8152","DOI":"10.1021\/acs.jmedchem.9b00919","volume":"62","author":"Z Wang","year":"2019","unstructured":"Wang Z, He N, Guo Z, Niu C, Song T, Guo Y, et al. Proteolysis targeting chimeras for the selective degradation of Mcl-1\/Bcl-2 derived from nonselective target binding ligands. J Med Chem. 2019;62:8152\u201363.","journal-title":"J Med Chem"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02756-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02756-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02756-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T09:10:34Z","timestamp":1763629834000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02756-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,19]]},"references-count":53,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["2756"],"URL":"https:\/\/doi.org\/10.1038\/s41375-025-02756-7","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,19]]},"assertion":[{"value":"2 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"DH: Advisory board, research support and honoraria by Bristol Myers Squibb and JAZZ. ES received honoraria from Amgen, BMS, Stemline, Sanofi, Incyte, Janssen, Takeda and JAZZ. RK received honoraria from Takeda, Janssen and Novartis. All other authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the local Ethics Committee of the University Medical Center G\u00f6ttingen (application number 02-02-14). Informed consent was obtained from all patients.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}