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.
Highlights
Long-term HSCs (LT-HSCs) in the adult have self-renewal capacity but reside in a quiescent state for most of their lifetime [1]
Hoxb8-fetal liver (FL) cells generated from Vav-BCL2-transgenic mice or mice lacking the key-apoptotic effectors Bax and Bak were protected from cell death, indicating initiation of caspase-dependent mitochondrial apoptosis after CHK1 inhibitors (CHK1i) treatment (Figs 1A and EV1A)
Though, Hoxb8-FL cells derived from the bone marrow of p53À/À mice were still highly susceptible to cell death indicating a minor contribution of p53 target genes to apoptosis upon checkpoint kinase 1 (CHK1) inhibition (Figs 1A and EV1A, left panel)
Summary
Long-term HSCs (LT-HSCs) in the adult have self-renewal capacity but reside in a quiescent state for most of their lifetime [1]. MPPs commit to the myeloid, lymphoid, or erythroid/ megakaryocyte lineage These transient amplifying cells with limited lineage potential provide the organism with all blood cells needed. CHK1 promotes the activity of MYT1 and WEE1 kinases that both inhibit CDK1 by phosphorylation, blocking transition from G2 to M-phase [16,17] Under these conditions, CHK1 can stabilize p53 by direct phosphorylation to tighten cell cycle arrest [18,19]. In the absence of p53, cells become highly dependent on CHK1 for cell cycle control, arrest, and repair of DNA damage [12,14], generating a vulnerability that is currently explored as a means to treat cancers with CHK1 inhibitors [11,20]
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