TY  - JOUR
AU  - Stalmann, Ursula S A
AU  - Ticconi, Fabio
AU  - Snoeren, Inge A M
AU  - Li, Ronghui
AU  - Gleitz, Helene
AU  - Cowley, Glenn
AU  - McConkey, Marie E
AU  - Wong, Aaron Benson
AU  - Schmitz, Stephani
AU  - Fuchs, Stijn N R
AU  - Sood, Shubhankar
AU  - Leimkühler, Nils Bastian
AU  - Martinez-Høyer, Sergio
AU  - Banjanin, Bella
AU  - Root, David E
AU  - Brümmendorf, Tim Henrik
AU  - Pearce, Juliette
AU  - Schuppert, Andreas
AU  - Bindels, Eric
AU  - Essers, Marieke
AU  - Heckl, Dirk
AU  - Stiehl, Thomas Peter
AU  - Costa, Ivan G
AU  - Ebert, Benjamin L
AU  - Schneider, Rebekka K
TI  - Genetic barcoding systematically comparing genes in del(5q) MDS reveals a central role for CSNK1A1 in clonal expansion.
JO  - Blood advances
VL  - 6
IS  - 6
SN  - 2473-9529
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2022-00071
SP  - 1780-1796
PY  - 2022
N1  - 2022 Mar 22;6(6):1780-1796
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:35016204
DO  - DOI:10.1182/bloodadvances.2021006061
UR  - https://inrepo02.dkfz.de/record/178445
ER  -