%0 Journal Article
%A Stalmann, Ursula S A
%A Ticconi, Fabio
%A Snoeren, Inge A M
%A Li, Ronghui
%A Gleitz, Helene
%A Cowley, Glenn
%A McConkey, Marie E
%A Wong, Aaron Benson
%A Schmitz, Stephani
%A Fuchs, Stijn N R
%A Sood, Shubhankar
%A Leimkühler, Nils Bastian
%A Martinez-Høyer, Sergio
%A Banjanin, Bella
%A Root, David E
%A Brümmendorf, Tim Henrik
%A Pearce, Juliette
%A Schuppert, Andreas
%A Bindels, Eric
%A Essers, Marieke
%A Heckl, Dirk
%A Stiehl, Thomas Peter
%A Costa, Ivan G
%A Ebert, Benjamin L
%A Schneider, Rebekka K
%T Genetic barcoding systematically comparing genes in del(5q) MDS reveals a central role for CSNK1A1 in clonal expansion.
%J Blood advances
%V 6
%N 6
%@ 2473-9529
%C Washington, DC
%I American Society of Hematology
%M DKFZ-2022-00071
%P 1780-1796
%D 2022
%Z 2022 Mar 22;6(6):1780-1796
%X How genetic haploinsufficiency contributes to the clonal dominance of hematopoietic stem cells (HSC) in del(5q) myelodysplastic syndrome (MDS) remains unresolved. Using a genetic barcoding strategy, a systematic comparison was carried out 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 pro-proliferative gene signature and HSCs 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. A crucial role for Csnk1a1 haploinsufficiency in the selective advantage of the 5q- HSC is therefore proposed. It is implemented by creation of a unique competitive advantage through increased HSC self-renewal and proliferation capacity, as well as increased fitness under inflammatory stress.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:35016204
%R 10.1182/bloodadvances.2021006061
%U https://inrepo02.dkfz.de/record/178445