Format

Send to

Choose Destination
Clin Cancer Res. 2018 Apr 1;24(7):1716-1726. doi: 10.1158/1078-0432.CCR-17-2344. Epub 2018 Jan 12.

Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse: An Exome Sequencing Study of 50 Patients.

Author information

1
Department of Medicine III, University Hospital, LMU Munich, München, Germany. pgreif@med.uni-muenchen.de.
2
German Cancer Consortium (DKTK), and.
3
German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Department of Medicine III, University Hospital, LMU Munich, München, Germany.
5
Anthropology and Human Genomics, Department Biology II, LMU Munich, Martinsried, Germany.
6
Institute for Medical Information Procesing, Biometry and Epidemiology (IBE), LMU Munich, München, Germany.
7
Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, München, Germany.
8
Divison of Hematology and Oncology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, and Campus Virchow, Berlin, Germany.
9
Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand.
10
Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany.
11
Department of Medicine A -Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
#
Contributed equally

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.

PMID:
29330206
DOI:
10.1158/1078-0432.CCR-17-2344
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center