Abstract
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. 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. 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. 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.
Highlights
Activation of the RAS pathway plays a major role in cancer cells
RAS mutations lead to a resistance of the Ras proteins to signaling provided by GTPase activating proteins remaining in the active GTP-bound state [2, 3]
Mononuclear cells were prepared and cryopreserved exactly as it is described for acute myeloid leukemia (AML) blast samples
Summary
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. 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. RAS mutations lead to a resistance of the Ras proteins to signaling provided by GTPase activating proteins remaining in the active GTP-bound state [2, 3]. In acute myelogenous leukemia (AML) activating point mutations could be shown to affect almost exclusively N-RAS and K-RAS at codons 12, 13, and 61 (5 – 7). These alterations were detected with varying frequencies (25-40%) and resemble one of the most common genetic alterations detected in AML
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
