Paolo Mazzeo,Sarah Mae Penir,Evgenii Shumilov,Sebastian Wolf,Björn Häupl,Katharina Markus,Katayoon Shirneshan,Katharina Rittscher,Elzbieta Brzuszkiewicz,Enver Aydilek,Hannes Treiber,Thomas Oellerich,Christina Ganster,Detlef Haase,Raphael Koch
{"title":"骨髓增生异常肿瘤和急性髓系白血病在治疗中的克隆进化和细胞凋亡抵抗:来自综合纵向分析的见解。","authors":"Paolo Mazzeo,Sarah Mae Penir,Evgenii Shumilov,Sebastian Wolf,Björn Häupl,Katharina Markus,Katayoon Shirneshan,Katharina Rittscher,Elzbieta Brzuszkiewicz,Enver Aydilek,Hannes Treiber,Thomas Oellerich,Christina Ganster,Detlef Haase,Raphael Koch","doi":"10.1038/s41375-025-02756-7","DOIUrl":null,"url":null,"abstract":"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 = 55) identified high-risk genetic alterations, while longitudinal analyses (n = 268, mean 8.7 [3-20] 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.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"24 1","pages":""},"PeriodicalIF":13.4000,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Clonal evolution and apoptosis resistance in myelodysplastic neoplasms and acute myeloid leukemia under treatment: insights from integrative longitudinal profiling.\",\"authors\":\"Paolo Mazzeo,Sarah Mae Penir,Evgenii Shumilov,Sebastian Wolf,Björn Häupl,Katharina Markus,Katayoon Shirneshan,Katharina Rittscher,Elzbieta Brzuszkiewicz,Enver Aydilek,Hannes Treiber,Thomas Oellerich,Christina Ganster,Detlef Haase,Raphael Koch\",\"doi\":\"10.1038/s41375-025-02756-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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 = 55) identified high-risk genetic alterations, while longitudinal analyses (n = 268, mean 8.7 [3-20] 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. 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Clonal evolution and apoptosis resistance in myelodysplastic neoplasms and acute myeloid leukemia under treatment: insights from integrative longitudinal profiling.
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 = 55) identified high-risk genetic alterations, while longitudinal analyses (n = 268, mean 8.7 [3-20] 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.
期刊介绍:
Title: Leukemia
Journal Overview:
Publishes high-quality, peer-reviewed research
Covers all aspects of research and treatment of leukemia and allied diseases
Includes studies of normal hemopoiesis due to comparative relevance
Topics of Interest:
Oncogenes
Growth factors
Stem cells
Leukemia genomics
Cell cycle
Signal transduction
Molecular targets for therapy
And more
Content Types:
Original research articles
Reviews
Letters
Correspondence
Comments elaborating on significant advances and covering topical issues