Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse : An Exome Sequencing Study of 50 Patients
©2018 American Association for Cancer Research..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 24(2018), 7 vom: 01. Apr., Seite 1716-1726 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Greif, Philipp A [VerfasserIn] |
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| Links: |
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| Themen: |
04079A1RDZ |
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| Anmerkungen: |
Date Completed 27.09.2019 Date Revised 07.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-17-2344 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM279925093 |
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| 100 | 1 | |a Greif, Philipp A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse |b An Exome Sequencing Study of 50 Patients |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Completed 27.09.2019 | ||
| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2018 American Association for Cancer Research. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Hartmann, Luise |e verfasserin |4 aut | |
| 700 | 1 | |a Vosberg, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Stief, Sophie M |e verfasserin |4 aut | |
| 700 | 1 | |a Mattes, Raphael |e verfasserin |4 aut | |
| 700 | 1 | |a Hellmann, Ines |e verfasserin |4 aut | |
| 700 | 1 | |a Metzeler, Klaus H |e verfasserin |4 aut | |
| 700 | 1 | |a Herold, Tobias |e verfasserin |4 aut | |
| 700 | 1 | |a Bamopoulos, Stefanos A |e verfasserin |4 aut | |
| 700 | 1 | |a Kerbs, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Jurinovic, Vindi |e verfasserin |4 aut | |
| 700 | 1 | |a Schumacher, Daniela |e verfasserin |4 aut | |
| 700 | 1 | |a Pastore, Friederike |e verfasserin |4 aut | |
| 700 | 1 | |a Bräundl, Kathrin |e verfasserin |4 aut | |
| 700 | 1 | |a Zellmeier, Evelyn |e verfasserin |4 aut | |
| 700 | 1 | |a Ksienzyk, Bianka |e verfasserin |4 aut | |
| 700 | 1 | |a Konstandin, Nikola P |e verfasserin |4 aut | |
| 700 | 1 | |a Schneider, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Graf, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Krebs, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Blum, Helmut |e verfasserin |4 aut | |
| 700 | 1 | |a Neumann, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Baldus, Claudia D |e verfasserin |4 aut | |
| 700 | 1 | |a Bohlander, Stefan K |e verfasserin |4 aut | |
| 700 | 1 | |a Wolf, Stephan |e verfasserin |4 aut | |
| 700 | 1 | |a Görlich, Dennis |e verfasserin |4 aut | |
| 700 | 1 | |a Berdel, Wolfgang E |e verfasserin |4 aut | |
| 700 | 1 | |a Wörmann, Bernhard J |e verfasserin |4 aut | |
| 700 | 1 | |a Hiddemann, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Spiekermann, Karsten |e verfasserin |4 aut | |
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