Clinical cancer research : an official journal of the American Association for Cancer Research · 2018
Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse: An Exome Sequencing Study of 50 Patients.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Greif Philipp A, Hartmann Luise, Vosberg Sebastian, Stief Sophie M, Mattes Raphael, Hellmann Ines, Metzeler Klaus H, Herold Tobias, Bamopoulos Stefanos A, Kerbs Paul, Jurinovic Vindi, Schumacher Daniela, Pastore Friederike, Bräundl Kathrin, Zellmeier Evelyn, Ksienzyk Bianka, Konstandin Nikola P, Schneider Stephanie, Graf Alexander, Krebs Stefan, Blum Helmut, Neumann Martin, Baldus Claudia D, Bohlander Stefan K, Wolf Stephan, Görlich Dennis, Berdel Wolfgang E, Wörmann Bernhard J, Hiddemann Wolfgang, Spiekermann Karsten
Аннотация
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.