Fig. 2.

Trametinib inhibits leukemic blast viability in vitro and in vivo and also during cytogenetic and molecular clonal evolution. a Trametinib inhibits leukemic blast viability in vitro in a dose-dependent manner. b siRNA-mediated knock-down of NRAS decreases in vitro blast viability (horizontal red bar = 95 % percentile. c Trametinib therapy correlates with partial remission of leukemic blasts. Blast counts (black line) decreased when on trametinib therapy (red shaded boxes) following AML relapse after standard induction therapy. Note the non-linear time scale. d Karyotyping demonstrates clonal evolution before and during trametinib therapy. e Targeted massively parallel sequencing demonstrates persistent NRAS and TP53 missense point mutations before and during trametinib therapy; WT1 mutations were identified at the time of germ cell tumor relapse. Identical NRAS and TP53 mutations were identified by targeted sequencing analysis of the patient’s mediastinal germ cell tumor