CHEK2 loss endows chemotherapy resistance to hematopoietic stem cells.

Individuals with history of chemo- or radiotherapy frequently exhibit somatic mosaicism in the blood, often involving mutations in genes responsible for DNA damage responses (DDR), such as CHEK2. However, the mechanisms by which CHEK2 mutations promote the expansion of mutant cells following chemo- or radiotherapy remain poorly understood. Here, we demonstrate that loss of CHEK2 confers resistance to chemotherapy in hematopoietic stem and progenitor cells (HSPCs). Through a CRISPR-based screen, we identified CHEK2 as a gene whose loss enhances resistance to cytotoxic chemotherapies. A complementary drug screen revealed that CHEK2-mutant cells are also resistant to DNA hypomethylating agents. Chek2-deficient HSPCs persist in vivo following chemotherapy exposure and exhibit elevated levels of DNA damage compared to wild-type cells. Our findings establish that CHEK2 loss promotes chemoresistance in HSPCs, offering new insights into the role of CHEK2 in therapy-related clonal hematopoiesis observed in cancer patients.