MEK inhibition prolongs survival in mice transplanted with Nras^G12D AML. (A) Survival of secondary recipient mice engrafted with 2 transplantable MPNs that were treated with PD901 (n = 8), GDC-0941 (n = 8), a combination of PD901 and GDC-0941 (n = 8), or control vehicle (n = 10). PD901 significantly prolonged the survival of transplant recipients (P = .0009). (B) Survival of recipient mice transplanted with 3 independent aggressive Nras^G12D AML lines treated with PD901 (n = 11), GDC-0941 (n = 11), a combination of PD901 and GDC-0941 (n = 8), or the control vehicle (n = 9). PD901 significantly prolonged the survival of transplant recipients (P = .0003). (C) Southern blot analysis of AML #6768 reveals an identical pattern of retroviral integrations in recipients treated with PD901 compared with controls. (D) WT mice treated with vehicle, PD901 (5 mg/kg), or trametinib (0.5 mg/kg) were euthanized at time 0 and 2, 8, and 24 hours, BM was collected, and c-Kit⁺ cells were assayed for ERK phosphorylation (pERK) under basal conditions and after stimulation with stem cell factor (SCF). (E) Survival of recipient mice transplanted with the 3 aggressive Nras^G12D AMLs shown in panel C treated with 0.5 mg/kg per day trametinib (n = 12) or the control vehicle (n = 10) demonstrating a significant improvement in overall survival (P = .0063).