title: Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia.
abstract: 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.
authors.affiliation: Department of Clinical Genetics, Section of Hematology/Oncology 4052, Juliane Marie Center, Rigshospitalet, Copenhagen, Denmark. Debesc@hfs.fo
authors.forename: D H
authors.initials: DH
authors.lastname: Christiansen
authors.forename: M K
authors.initials: MK
authors.lastname: Andersen
authors.forename: F
authors.initials: F
authors.lastname: Desta
authors.forename: J
authors.initials: J
authors.lastname: Pedersen-Bjergaard
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000235:genetics*; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins / Q000235:genetics
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D051941:fms-Like Tyrosine Kinase 3; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins