title: Activation of the RAS pathway is predictive for a chemosensitive phenotype of acute myelogenous leukemia blasts.
abstract: OBJECTIVE
  Activation of the RAS pathway plays a major role in cancer cells. In acute myeloid leukemia (AML), mutations of the RAS genes cause an intrinsic activation of this pathway. Until now, clinical studies could not find clear association of RAS mutations with the clinical outcome after AML therapy. This could be due to alternative initiating events for activation of the RAS pathway like constitutive tyrosine kinase activation or mutations in Ras-regulating genes.
  
  
  METHODS
  In total, 191 AML patients (126 as training population and 65 as test population) were studied for Ras activity with a glutathione S-transferase pull-down assay using Raf binding of activated Ras.
  
  
  RESULTS
  AML samples showed a wide range of Ras activity values, which was in contrast to normal bone marrow donors who showed no or very limited Ras activity. Using a Ras binding score based on semiquantitative Western blotting, we defined patients with strong Ras activity and compared Ras activity with RAS mutation. Surprisingly, only a minority of RAS mutated AML samples (22.2%) showed strong Ras activity, whereas 25 patients presented strong Ras activity in the absence of RAS mutations. Clinical outcome did not show differences according to RAS mutations. In contrast, Ras activity predicted for a high response rate (P <0.05) and proved to be an independent factor for overall survival rate (P <0.05) in younger AML patients receiving high-dose 1-beta-D-arabinofuranosylcytosine as induction therapy.
  
  
  CONCLUSIONS
  The data highlight the role for alternative pathways of Ras activation without RAS mutations. Intrinsically activated Ras seems to increase sensitivity of the AML blast to high-dose 1-beta-D-arabinofuranosylcytosine therapy.
authors.affiliation: Medical Clinic and Policlinic I, University Hospital of the Technical University, Dresden, Germany. ilmer@mk1.med.tu-dresden.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Illmer
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Anke
authors.initials: A
authors.lastname: Fredersdorf
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stadler
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubauer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Markus
authors.initials: M
authors.lastname: Schaich
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003561:Cytarabine / Q000627:therapeutic use; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D018631:ras Proteins