Mutations of the FLT3, c-KIT, c-FMS, KRAS, NRAS, BRAF and CEBPA genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal-transduction pathway are frequent in acute myeloid leukemia (AML). We examined 140 patients with therapy-related myelodysplasia or AML (t-MDS/t-AML) for point mutations of these seven genes. In all, 11 FLT3, two c-KIT, seven KRAS, eight NRAS and three BRAF mutations were identified in 29 patients (21%). All but one patient with a FLT3 mutation presented with t-AML (P= 0.0002). Furthermore, FLT3 mutations were significantly associated with previous radiotherapy without chemotherapy (P= 0.03), and with a normal karyotype (P= 0.004), but inversely associated with previous therapy with alkylating agents (P= 0.003) and with− 7/7q−(P= 0.001). RAS mutations were associated with AML1 point mutations (P= 0.046) and with progression from t-MDS to t-AML (P= 0.008). Noteworthy, all three patients with BRAF mutations presented as t-AML of M5 subtype with t (9; 11)(p22; q23) and MLL-rearrangement (P= 0.01). In t-AML RAS/BRAF mutations were significantly associated with a very short survival (P= 0.017). Half of the patients with a mutation in the RTK/RAS-BRAF signal-transduction pathway (denoted ‘class-I’mutations) simultaneously disclosed mutation of a hematopoietic transcription factor (denoted ‘class-II’mutations)(P= 0.046) suggesting their cooperation in leukemogenesis.