Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Greif, PA; Hartmann, L; Vosberg, S; Stief, SM; Mattes, R; Hellmann, I; Metzeler, KH; Herold, T; Bamopoulos, SA; Kerbs, P; Jurinovic, V; Schumacher, D; Pastore, F; Bräundl, K; Zellmeier, E; Ksienzyk, B; Konstandin, NP; Schneider, S; Graf, A; Krebs, S; Blum, H; Neumann, M; Baldus, CD; Bohlander, SK; Wolf, S; Görlich, D; Berdel, WE; Wörmann, BJ; Hiddemann, W; Spiekermann, K.
Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse: An Exome Sequencing Study of 50 Patients.
Clin Cancer Res. 2018; 24(7): 1716-1726.
Doi: 10.1158/1078-0432.CCR-17-2344
Web of Science
PubMed
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- Führende Autor*innen der Med Uni Graz
- Vosberg Sebastian
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- Abstract:
- Purpose: To study mechanisms of therapy resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations.Experimental Design: We performed exome sequencing of matched diagnosis, remission, and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters.Results: Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of KDM6A constituting a mechanism of cytarabine resistance. Low KDM6A expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing preleukemic lesions were observed in 48% of patients. The persistence of DNMT3A mutations correlated with shorter time to relapse.Conclusions: Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML. Clin Cancer Res; 24(7); 1716-26. ©2018 AACR. ©2018 American Association for Cancer Research.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult -
- Aged -
- Aged, 80 and over -
- Cell Line -
- Cytarabine - pharmacology
- Cytogenetics - methods
- DNA (Cytosine-5-)-Methyltransferases - genetics
- Drug Resistance - drug effects
- Drug Resistance - genetics
- Epigenesis, Genetic - drug effects
- Epigenesis, Genetic - genetics
- Exome - genetics
- Female -
- Histone Demethylases - genetics
- Humans -
- Leukemia, Myeloid, Acute - drug therapy
- Leukemia, Myeloid, Acute - genetics
- Male -
- Middle Aged -
- Mutation - drug effects
- Mutation - genetics
- Recurrence -
- Remission Induction - methods
- Whole Exome Sequencing - methods
- Young Adult -