Collaborative effect of Csnk1a1 haploinsufficiency and mutant p53 in Myc induction can promote leukemic transformation

Stijn N.R. Fuchs, Ursula S.A. Stalmann, Inge A.M. Snoeren, Eric Bindels, Stephani Schmitz, Bella Banjanin, Remco M. Hoogenboezem, Stanley van Herk, Mohamed Saad, Wencke Walter, Torsten Haferlach, Lancelot Seillier, Julio Saez-Rodriguez, Aurélien J.F. Dugourd, Kjong Van Lehmann, Yinon Ben-Neriah, Hélène F.E. Gleitz, Rebekka K. Schneider*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

It is still not fully understood how genetic haploinsufficiency in del(5q) myelodysplastic syndrome (MDS) contributes to malignant transformation of hematopoietic stem cells. We asked how compound haploinsufficiency for Csnk1a1 and Egr1 in the common deleted region on chromosome 5 affects hematopoietic stem cells. Additionally, Trp53 was disrupted as the most frequently comutated gene in del(5q) MDS using CRISPR/Cas9 editing in hematopoietic progenitors of wild-type (WT), Csnk1a1–/+, Egr1–/+, Csnk1a1/Egr1–/+ mice. A transplantable acute leukemia only developed in the Csnk1a1–/+ Trp53–edited recipient. Isolated blasts were indefinitely cultured ex vivo and gave rise to leukemia after transplantation, providing a tool to study disease mechanisms or perform drug screenings. In a small-scale drug screening, the collaborative effect of Csnk1a1 haploinsufficiency and Trp53 sensitized blasts to the CSNK1 inhibitor A51 relative to WT or Csnk1a1 haploinsufficient cells. In vivo, A51 treatment significantly reduced blast counts in Csnk1a1 haploinsufficient/Trp53 acute leukemias and restored hematopoiesis in the bone marrow. Transcriptomics on blasts and their normal counterparts showed that the derived leukemia was driven by MAPK and Myc upregulation downstream of Csnk1a1 haploinsufficiency cooperating with a downregulated p53 axis. A collaborative effect of Csnk1a1 haploinsufficiency and p53 loss on MAPK and Myc upregulation was confirmed on the protein level. Downregulation of Myc protein expression correlated with efficient elimination of blasts in A51 treatment. The “Myc signature” closely resembled the transcriptional profile of patients with del(5q) MDS with TP53 mutation.

Original languageAmerican English
Pages (from-to)766-779
Number of pages14
JournalBlood advances
Volume8
Issue number3
DOIs
StatePublished - 13 Feb 2024

Bibliographical note

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© 2024 by The American Society of Hematology.

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