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Stalmann, Ursula S. A.; Ticconi, Fabio; Snoeren, Inge A. M.; Li, Ronghui; Gleitz, Hélène F. E.; Cowley, Glenn S.; McConkey, Marie E.; Wong, Aaron B.; Schmitz, Stephani; Fuchs, Stijn N. R.; Sood, Shubhankar; Leimkühler, Nils B.; Martinez-Høyer, Sergio; Banjanin, Bella; Root, David; Brümmendorf, Tim H.; Pearce, Juliette E.; Schuppert, Andreas; Bindels, Eric M. J.; Essers, Marieke A.; Heckl, Dirk; Stiehl, Thomas; Costa, Ivan G.; Ebert, Benjamin L.;

Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion

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  • Medientyp: E-Artikel
  • Titel: Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion
  • Beteiligte: Stalmann, Ursula S. A.; Ticconi, Fabio; Snoeren, Inge A. M.; Li, Ronghui; Gleitz, Hélène F. E.; Cowley, Glenn S.; McConkey, Marie E.; Wong, Aaron B.; Schmitz, Stephani; Fuchs, Stijn N. R.; Sood, Shubhankar; Leimkühler, Nils B.; Martinez-Høyer, Sergio; Banjanin, Bella; Root, David; Brümmendorf, Tim H.; Pearce, Juliette E.; Schuppert, Andreas; Bindels, Eric M. J.; Essers, Marieke A.; Heckl, Dirk; Stiehl, Thomas; Costa, Ivan G.; Ebert, Benjamin L.;
  • Erschienen: American Society of Hematology, 2022
  • Erschienen in: Blood Advances, 6 (2022) 6, Seite 1780-1796
  • Sprache: Englisch
  • DOI: 10.1182/bloodadvances.2021006061
  • ISSN: 2473-9529; 2473-9537
  • Entstehung:
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  • Beschreibung: 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.
  • Zugangsstatus: Freier Zugang