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. 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 language | English |
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Pages (from-to) | 1780-1796 |
Number of pages | 17 |
Journal | Blood advances |
Volume | 6 |
Issue number | 6 |
DOIs | |
Publication status | Published - 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 grantPublisher Copyright: © 2022 by The American Society of Hematology.