Hyperactivation of p53 mediates hematopoietic deficiency and increased lethality in Hdac8-deficient mice challenged with serial 5-FU. (A) Schematic of experimental design. Two-month-old mice were induced by 7 doses of poly (I:C) and complete blood count analyzed 2 weeks later (time 0), followed by 5-FU (100 mg/kg) injection every 7 days. Mice were monitored for survival or analyzed for phenotypic HSPC populations by flow cytometry. (B) Relative expression of p53 and p53 target genes Bax, Bid, Gadd45b, Puma Stag1, and Cdkn1a in control (Ctrl) or Hdac8^Δ/Δ LT-HSCs 2 days after treatment with 5-FU (100 mg/kg). (C) Frequency of activated caspase 3⁺ cells in phenotypic HSPC subpopulations 2 days after 5-FU treatment in Ctrl or Hdac8^Δ/Δ mice (n = 3). Shown is mean ± SEM. (D-F) Weekly white blood cell (WBC), red blood cell (RBC), and platelet (PLT) counts of 5-FU–treated mice (Ctrl, n = 34; Hdac8^Δ/Δ, n = 30; Hdac8^Δ/Δ/p53ER^KI/KI, n = 7; p53ER^KI/KI, n = 10). Mean ± SEM is shown. (G) Kaplan-Meier survival curves of serial 5-FU–treated Ctrl (n = 34), Hdac8^Δ/Δ (n = 30), Hdac8^Δ/Δ/p53ER^KI/KI (n = 7), or p53ER^KI/KI (n = 10) mice. *P < .05, **P < .01, ***P < .001.