Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure.
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.
Department of Hematology and Oncology.
Maximilian
M
Mossner
Department of Hematology and Oncology.
Johann-Christoph
JC
Jann
Department of Hematology and Oncology.
Janina
J
Wittig
Department of Hematology and Oncology.
Florian
F
Nolte
Department of Hematology and Oncology.
Stephanie
S
Fey
Department of Hematology and Oncology.
Verena
V
Nowak
Department of Hematology and Oncology.
Julia
J
Obländer
Department of Hematology and Oncology.
Jovita
J
Pressler
Department of Hematology and Oncology.
Iris
I
Palme
Department of Hematology and Oncology.
Christina
C
Xanthopoulos
Department of Hematology and Oncology.
Tobias
T
Boch
Department of Hematology and Oncology.
Georgia
G
Metzgeroth
Department of Orthopedics, and.
Henning
H
Röhl
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
Stephanie H
SH
Witt
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
Helene
H
Dukal
Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany;
Corinna
C
Klein
Imaging and Cytometry Core Facility, German Cancer Research Center, Heidelberg, Germany;
Steffen
S
Schmitt
Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany;
Patrick
P
Gelß
University Hospital Carl Gustav Carus, Dresden, Germany;
Uwe
U
Platzbecker
University Hospital Carl Gustav Carus, Dresden, Germany;
Ekaterina
E
Balaian
Department of Hematology and Oncology.
Alice
A
Fabarius
Laboratory for Functional Genome Analysis, Gene Center, Munich, Germany;
Helmut
H
Blum
Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, German Red Cross Blood Service, Baden-Württemberg-Hessen, Germany;
Torsten J
TJ
Schulze
Munich Leukemia Laboratory, Munich, Germany;
Manja
M
Meggendorfer
Munich Leukemia Laboratory, Munich, Germany;
Claudia
C
Haferlach
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.
Andreas
A
Trumpp
Department of Hematology and Oncology.
Wolf-Karsten
WK
Hofmann
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.
Hind
H
Medyouf
Department of Hematology and Oncology.
Daniel
D
Nowak
D000818:Animals; D005260:Female; D006410:Hematopoiesis / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000628:therapy*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000628:therapy*; D009368:Neoplasm Transplantation