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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)
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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. Csnk1a12/1 multipotent progenitors showed a proproliferative gene signature and HSCs showed a downregulation of inflammatory signaling/immune response. In validation experiments, Csnk1a12/1 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.

Original languageEnglish
Pages (from-to)1780-1796
Number of pages17
JournalBlood advances
Issue number6
Publication statusPublished - 22 Mar 2022

Bibliographical note

Funding Information: This work was supported by grants from the MPN foundation (2017 MPNRF/LLS Award), a KWF Kankerbestrijding young investigator grant (11031/2017–1, Bas Mulder Award; Dutch Cancer Foundation) and a grant from the European Research Council (ERC) (deFIBER;ERC-StG 757339) to R.K.S., and by a grant from the NIH (R01 HL082945) to B.L.E. T.H.B., I.C. and R.K.S. are part of the clinical research unit CRU344 supported by the German Research Foundation (DeutscheForschungsge-meinschaft, DFG). I.C. and R.K.S. are members of the E:MED Consortia Fibromap, funded by the German Ministry of Education and Science (BMBF). I.C. was supported by an IZKF grant

Publisher Copyright: © 2022 by The American Society of Hematology.


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