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Blood. 2016 Sep 1;128(9):1246-59. doi: 10.1182/blood-2015-11-679167. Epub 2016 Jun 6.

Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure.

Author information

1
Department of Hematology and Oncology.
2
Department of Orthopedics, and.
3
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
4
Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany;
5
Imaging and Cytometry Core Facility, German Cancer Research Center, Heidelberg, Germany;
6
Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany;
7
University Hospital Carl Gustav Carus, Dresden, Germany;
8
Laboratory for Functional Genome Analysis, Gene Center, Munich, Germany;
9
Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, German Red Cross Blood Service, Baden-Württemberg-Hessen, Germany;
10
Munich Leukemia Laboratory, Munich, Germany;
11
Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; and.
12
Department of Hematology and Oncology, Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany; Georg-Speyer Haus Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany.

Abstract

Clonal evolution is believed to be a main driver for progression of various types of cancer and implicated in facilitating resistance to drugs. However, the hierarchical organization of malignant clones in the hematopoiesis of myelodysplastic syndromes (MDS) and its impact on response to drug therapy remain poorly understood. Using high-throughput sequencing of patient and xenografted cells, we evaluated the intratumoral heterogeneity (n= 54) and reconstructed mutational trajectories (n = 39) in patients suffering from MDS (n = 52) and chronic myelomonocytic leukemia-1 (n = 2). We identified linear and also branching evolution paths and confirmed on a patient-specific level that somatic mutations in epigenetic regulators and RNA splicing genes frequently constitute isolated disease-initiating events. Using high-throughput exome- and/or deep-sequencing, we analyzed 103 chronologically acquired samples from 22 patients covering a cumulative observation time of 75 years MDS disease progression. Our data revealed highly dynamic shaping of complex oligoclonal architectures, specifically upon treatment with lenalidomide and other drugs. Despite initial clinical response to treatment, patients' marrow persistently remained clonal with rapid outgrowth of founder-, sub-, or even fully independent clones, indicating an increased dynamic rate of clonal turnover. The emergence and disappearance of specific clones frequently correlated with changes of clinical parameters, highlighting their distinct and far-reaching functional properties. Intriguingly, increasingly complex mutational trajectories are frequently accompanied by clinical progression during the course of disease. These data substantiate a need for regular broad molecular monitoring to guide clinical treatment decisions in MDS.

PMID:
27268087
DOI:
10.1182/blood-2015-11-679167
[Indexed for MEDLINE]
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