Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion
Blood Advances, vol. 6, pp. 1780–1796
Abstract
How genetic haploinsufficiency contributes to the clonal dominance of hematopoietic stem cells (HSCs) in del(5q) myelodysplastic syndrome (MDS) remains unresolved. Using a genetic barcoding strategy, we performed a systematic comparison on genes implicated in the pathogenesis of del(5q) MDS in direct competition with each other and wild-type (WT) cells with single-clone resolution. Csnk1a1 haploinsufficient HSCs expanded (oligo)clonally and outcompeted all other tested genes and combinations. Csnk1a1-/+ multipotent progenitors showed a proproliferative gene signature and HSCs showed a downregulation of inflammatory signaling/immune response. In validation experiments, Csnk1a1-/+ HSCs outperformed their WT counterparts under a chronic inflammation stimulus, also known to be caused by neighboring genes on chromosome 5. We therefore propose a crucial role for Csnk1a1 haploinsufficiency in the selective advantage of 5q-HSCs, implemented by creation of a unique competitive advantage through increased HSC self-renewal and proliferation capacity, as well as increased fitness under inflammatory stress.
Authors 25
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Developmental Biology and
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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Affiliation as printed
Institute for Computational Genomics, Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany;
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Developmental Biology and
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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Affiliation as printed
Institute for Computational Genomics, Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany;
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Developmental Biology and
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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Broad Institute · Harvard University · Massachusetts Institute of Technology
Affiliation as printed
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA;
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Affiliation as printed
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
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Affiliation as printed
Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands;
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Developmental Biology and
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Developmental Biology and
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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German Cancer Research Center · Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Affiliation as printed
German Cancer Research Center (DKFZ), Heidelberg, Germany;
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GMBH), Heidelberg, Germany;
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Developmental Biology and
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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Broad Institute · Harvard University · Massachusetts Institute of Technology
Affiliation as printed
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA;
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Affiliation as printed
Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation,
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Institute for Biomedical Engineering
Affiliation as printed
Department of Cell Biology, Institute for Biomedical Engineering, Faculty of Medicine, and
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Affiliation as printed
Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany;
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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German Cancer Research Center · Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Affiliation as printed
German Cancer Research Center (DKFZ), Heidelberg, Germany;
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GMBH), Heidelberg, Germany;
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Martin Luther University Halle-Wittenberg
Affiliation as printed
Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany;
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Affiliation as printed
Institute for Computational Biomedicine-Disease Modeling, Faculty of Medicine, RWTH Aachen University, Aachen, Germany; and
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Affiliation as printed
Institute for Computational Genomics, Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany;
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Howard Hughes Medical Institute · Dana-Farber Cancer Institute
Affiliation as printed
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
Howard Hughes Medical Institute, Boston, MA
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Erasmus MC · Institute for Biomedical Engineering · Erasmus MC Cancer Institute
Affiliation as printed
Department of Cell Biology, Institute for Biomedical Engineering, Faculty of Medicine, and
Department of Developmental Biology and
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;
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