PPM1D mutations contribute to CH by suppressing the DDR and enhancing cell survival. (A) Schematic of the DDR and the role of PPM1D in dephosphorylating the positive regulators of DDR. (B) After 1 round of cisplatin treatment, 16% more PPM1D-mutant cells were alive. (C) If mutant cells start as 10% of the population, after each round of cisplatin, 16% more cells are surviving. This compounds in each round such that the proportion climbs to ∼30% after only 3 rounds. In patients, the mutant cells would be represented as 1 or a few HSCs but would still increase dramatically over time.