Figure 5. Effects of MK-2206 in Kras^D12 hematopoietic progenitors.

(A,B) Frequencies of hematopoietic stem and progenitor cell populations in the bone marrows of Kras^D12 and control mice were determined by flow cytometry after treatment with vehicle, PD0325901, MK-2206, or both agents for up to 8 weeks. 5 to 13 mice were analyzed in each group, and data were analyzed as described for Figure 4D, comparing vehicle treated Kras^D12 mice to vehicle treated control mice, and drug treated mice to respective vehicle treated mice.

(C) Bone marrow cells were harvested from Kras^D12 and control mice after treatment with MK-2206, MK-2206+PD0325901, or vehicle for 5 weeks, and plated in methylcellulose (5×10⁴ cells per culture) containing 0.01–10 ng/mL GM-CSF. Myeloid colony numbers were normalized to the saturating GM-CSF concentration to determine the dose-response curve. Mean ± s.e.m. are displayed for each data point.

(D) CFU-GM from untreated Kras^D12 or control mice were grown in the presence of saturating GM-CSF (10 ng/mL) and 1–100 µM MK-2206 or DMSO 0.2% (n=4). Colony numbers were normalized to DMSO control; mean ± s.e.m. are displayed. CFU-GM from Kras^D12 mice were more sensitive to MK-2206 (p = 0.029 by permutation significance testing).