Checkpoint kinase 1 is essential for fetal and adult hematopoiesis

Abstract

Checkpoint kinase 1 (CHK1) is critical for S‐phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumor cells have developed a strong dependence on CHK1 for survival, and hence, this kinase has developed into a promising drug target. Chk1 deficiency in mice results in blastocyst death due to G2/M checkpoint failure showing that it is an essential gene and may be difficult to target therapeutically. Here, we show that chemical inhibition of CHK1 kills murine and human hematopoietic stem and progenitor cells (HSPCs) by the induction of BCL2‐regulated apoptosis. Cell death in HSPCs is independent of p53 but requires the BH3‐only proteins BIM, PUMA, and NOXA. Moreover, Chk1 is essential for definitive hematopoiesis in the embryo. Noteworthy, cell death inhibition in HSPCs cannot restore blood cell formation as HSPCs lacking CHK1 accumulate DNA damage and stop dividing. Moreover, conditional deletion of Chk1 in hematopoietic cells of adult mice selects for blood cells retaining CHK1, suggesting an essential role in maintaining functional hematopoiesis. Our findings establish a previously unrecognized role for CHK1 in establishing and maintaining hematopoiesis.

Small molecule inhibitors and a kinase-dead expressing mouse model demonstrate that the kinase activity of Chk1 is essential for mouse embryos and cancer cells

“…Unfortunately, we were unable to confirm this since Chek1 heterozygous mice was not available at the time when we found that a heterozygous kinase-dead expressing Chk1 mouse did not exhibit any aging-related defects in erythropoiesis. Nevertheless, recently Schuler et al also demonstrated that whereas conditional deletion of both alleles of Chek1 using a Vav-Cre driver impaired hematopoiesis, heterozygous deletion had no impact on hematopoiesis or erythropoiesis (36). These data and ours argue that Chk1 is not haploinsufficient for erythropoiesis.…”

Exploration of Prognostic Biomarkers and Therapeutic Targets in The Microenvironment of Bladder Cancer Based on CXC Chemokines

“…Our study provided evidence that there is an association between CXC chemokines and the NF-κB signaling pathway during BLCA tumorigenesis and development. Our results also suggested Src family tyrosine kinases (LCK and LYN), PKN1, PRKG1, and CHEK1 might be the targets of the differential CXC chemokines, which play important roles in cell growth, division, migration, and survival signaling pathways [66][67][68][69], and mediate the carcinogenesis of several tumors [70][71][72]. Therefore, these differentially expressed CXC chemokines might modulate BLCA development and progression dependent on the above-mentioned signaling pathways by regulating these kinases.…”

FANCD2 Alleviates Physiologic Replication Stress in Fetal Liver HSC

“…3). This may be relevant for the critical role Chk1 plays in maintaining self-renewal, safeguarding HSC pool integrity, and minimizing mutational burden (Schuler et al, 2019).…”

“…The fetal liver (FL) takes on a crucial role for rapid clonal expansion during development. Not surprisingly, HSC rely on intact cell cycle checkpoints and DNA repair pathways to minimize the potential mutational burden in a highly proliferative HSC pool (Beerman et al, 2014;Schuler et al, 2019).…”