Impaired DNA Replication within Progenitor Cell Pools Promotes Leukemogenesis (original) (raw)
Figure 4
E2f1/_E2f_2 Loss Promotes Bcr-Abl-Mediated Leukemias
(A and B) E2f1+2+ or DKO mouse c-Kit+ cells were transduced with MSCV-Bcr-Abl and transplanted as in Figure 2, except that in (B) a higher initial transduction efficiency was obtained (23.2% for E2f1+2+ and 24.1% for DKO). Initial transduction efficiencies for (A) were the same as in Figure 2. Untransduced competitors were included as described in Figure 2, except that for the experiments shown in (B), competitors were c-Kit+-purified BM cells cultured in parallel to the transduced cultures but not infected, and each recipient mouse received 1.5 × 105 untransduced c-Kit+ competitors combined with 1.4 × 106_Bcr-Abl_-transduced progenitors. Kaplan-Meier curves are shown for both experiments. Mice were sacrificed when moribund, all with splenomegaly and lymphadenopathy. No mice transplanted with vector-expressing cells developed leukemia (unpublished data). The Kaplan-Meier curves for Bcr-Abl/DKO are statistically different from the Bcr-Abl/ E2f1+2+ (p < 0.001 for [A] and p < 0.0001 for [B]) and Bcr-Abl/DKO + E2f1+2+ competitors (p < 0.001 for [A], p < 0.02 for [B]) curves.
(C) Peripheral blood, spleen, and BM from morbid leukemic Bcr-Abl BMT mice or from healthy vector BMT mice (from [B]) were analyzed for the expression of the indicated antigens and GFP by flow cytometry. Peripheral blood was analyzed 21 d post-BMT. The recipient of Bcr-Abl/DKO cells was sacrificed at 23 d and other recipients sacrificed at 29 d post-BMT. The mean fluorescence intensities (mfi) for peripheral B220+ cells are indicated.