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. Essers; Dirk Heckl; Thomas Stiehl; Ivan G. Costa; Benjamin L. Ebert; Rebekka K. Schneider

doi:10.1182/BLOODADVANCES.2021006061

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. Essers

Dirk Heckl, Thomas Stiehl, Ivan G. Costa, Benjamin L. Ebert, Rebekka K. Schneider^*

^*Corresponding author for this work

RWTH Aachen University
Broad Institute of MIT and Harvard
Dana-Farber Cancer Institute
German Cancer Research Center
Martin Luther University Halle-Wittenberg
Howard Hughes Medical Institute
Oncode Institute (Nederland)
Heidelberg Institute for Stem Cell Technology and Experimental Medicine GmbH (HI-STEM)
Erasmus MC Cancer Institute
Erasmus University Medical Centre

Research output: Contribution to journal › Article › Academic › peer-review

10 Citations (Scopus)

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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. Csnk1a1^2/1 multipotent progenitors showed a proproliferative gene signature and HSCs showed a downregulation of inflammatory signaling/immune response. In validation experiments, Csnk1a1^2/1 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
Pages (from-to)	1780-1796
Number of pages	17
Journal	Blood advances
Volume	6
Issue number	6
DOIs	https://doi.org/10.1182/BLOODADVANCES.2021006061
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 grant

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

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Stalmann, U. S. A., Ticconi, F., Snoeren, I. A. M., Li, R., Gleitz, H. F. E., Cowley, G. S., McConkey, M. E., Wong, A. B., Schmitz, S., Fuchs, S. N. R., Sood, S., Leimkuhler, N. B., Martinez-Høyer, S., Banjanin, B., Root, D., Brummendorf, T. H., Pearce, J. E., Schuppert, A., Bindels, E. M. J., ... Schneider, R. K. (2022). Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion. Blood advances, 6(6), 1780-1796. https://doi.org/10.1182/BLOODADVANCES.2021006061

@article{73fbd14528bf47d0a974f54f6099e58d,

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

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.",

author = "Stalmann, \{Ursula S.A.\} and Fabio Ticconi and Snoeren, \{Inge A.M.\} and Ronghui Li and Gleitz, \{H{\'e}l{\`e}ne F.E.\} and Cowley, \{Glenn S.\} and McConkey, \{Marie E.\} and Wong, \{Aaron B.\} and Stephani Schmitz and Fuchs, \{Stijn N.R.\} and Shubhankar Sood and Leimkuhler, \{Nils B.\} and Sergio Martinez-H{\o}yer and Bella Banjanin and David Root and Brummendorf, \{Tim H.\} and Pearce, \{Juliette E.\} and Andreas Schuppert and Bindels, \{Eric M.J.\} and Essers, \{Marieke A.\} and Dirk Heckl and Thomas Stiehl and Costa, \{Ivan G.\} and Ebert, \{Benjamin L.\} and Schneider, \{Rebekka K.\}",

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: {\textcopyright} 2022 by The American Society of Hematology.",

year = "2022",

month = mar,

day = "22",

doi = "10.1182/BLOODADVANCES.2021006061",

language = "English",

volume = "6",

pages = "1780--1796",

journal = "Blood advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "6",

}

Stalmann, USA, Ticconi, F, Snoeren, IAM, Li, R, Gleitz, HFE, Cowley, GS, McConkey, ME, Wong, AB , Schmitz, S , Fuchs, SNR, Sood, S, Leimkuhler, NB, Martinez-Høyer, S, Banjanin, B, Root, D, Brummendorf, TH, Pearce, JE, Schuppert, A, Bindels, EMJ, Essers, MA, Heckl, D, Stiehl, T, Costa, IG, Ebert, BL & Schneider, RK 2022, 'Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion', Blood advances, vol. 6, no. 6, pp. 1780-1796. https://doi.org/10.1182/BLOODADVANCES.2021006061

TY - JOUR

T1 - Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion

AU - Stalmann, Ursula S.A.

AU - Ticconi, Fabio

AU - Snoeren, Inge A.M.

AU - Li, Ronghui

AU - Gleitz, Hélène F.E.

AU - Cowley, Glenn S.

AU - McConkey, Marie E.

AU - Wong, Aaron B.

AU - Schmitz, Stephani

AU - Fuchs, Stijn N.R.

AU - Sood, Shubhankar

AU - Leimkuhler, Nils B.

AU - Martinez-Høyer, Sergio

AU - Banjanin, Bella

AU - Root, David

AU - Brummendorf, Tim H.

AU - Pearce, Juliette E.

AU - Schuppert, Andreas

AU - Bindels, Eric M.J.

AU - Essers, Marieke A.

AU - Heckl, Dirk

AU - Stiehl, Thomas

AU - Costa, Ivan G.

AU - Ebert, Benjamin L.

AU - Schneider, Rebekka K.

N1 - 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.

PY - 2022/3/22

Y1 - 2022/3/22

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85127597589

U2 - 10.1182/BLOODADVANCES.2021006061

DO - 10.1182/BLOODADVANCES.2021006061

M3 - Article

C2 - 35016204

AN - SCOPUS:85127597589

SN - 2473-9529

VL - 6

SP - 1780

EP - 1796

JO - Blood advances

JF - Blood advances

IS - 6

ER -

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

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