Accelerated loss of K3^−/− HSCs under hematopoietic stress. (A) Kaplan-Meier survival curves after serial BM transplantations. ***, P < 0.0001 by log-rank test. n = 42–55 recipients per genotype; nine independent experiments. (B) Second generation recipients transplanted with BM LSK CD150⁺ cells and host-type whole Spl cells. Mean percentages ± SD of donor-derived whole leukocytes (CD45⁺), myeloid cells (Gr-1⁺, Mac-1⁺, and Gr-1⁺Mac-1⁺), B cells (B220⁺), and T cells (CD3e⁺) shown in PB at the indicated times after transplantation. ***, P < 0.0001 by Mann-Whitney test. (C) Mean percentages ± SD of donor-derived HSPCs in BM of second generation recipients 11 wk after transplantation. ***, P < 0.0001 by Mann-Whitney test. (B and C) n = 23–28; four to five independent experiments. (D) Kaplan-Meier survival curve showing response of control and K3^fl/flRosa26^Cre-ERT2 chimeras (n = 7) to tamoxifen treatment. The dashed arrow indicates the median survival of tamoxifen-treated K3^fl/flRosa26^Cre-ERT2 chimeras. The control group consisted of K3^fl/flRosa26^Cre-ERT2 (without TAM, n = 4) and K3^fl/fl (with TAM, n = 7; or without TAM, n = 3) chimeras. *, P = 0.0385 by log-rank test. (E) Kaplan-Meier survival curve of K3^fl/flRosa26^Cre-ERT2 (n = 10) and control mice to 5-FU treatment. The control group contained K3^fl/flRosa26^Cre-ERT2 (without TAM, n = 7), K3^+/+Rosa26^Cre-ERT2 (with TAM, n = 6; or without TAM, n = 5), and K3^fl/fl (with TAM, n = 2; or without TAM, n = 2) mice. ***, P < 0.0001 by log-rank test.