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. 2009 Apr;88(4):319-24.
doi: 10.1007/s00277-008-0593-6. Epub 2008 Sep 11.

Determination of Ras-GTP and Ras-GDP in patients with acute myelogenous leukemia (AML), myeloproliferative syndrome (MPS), juvenile myelomonocytic leukemia (JMML), acute lymphocytic leukemia (ALL), and malignant lymphoma: assessment of mutational and indirect activation

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Determination of Ras-GTP and Ras-GDP in patients with acute myelogenous leukemia (AML), myeloproliferative syndrome (MPS), juvenile myelomonocytic leukemia (JMML), acute lymphocytic leukemia (ALL), and malignant lymphoma: assessment of mutational and indirect activation

D Raepple et al. Ann Hematol. 2009 Apr.

Abstract

The 21-kD protein Ras of the low-molecular-weight GTP-binding (LMWG) family plays an important role in transduction of extracellular signals. Ras functions as a 'molecular switch' in transduction of signals from the membrane receptors of many growth factors, cytokines, and other second messengers to the cell nucleus. Numerous studies have shown that in multiple malignant tumors and hematopoietic malignancies, faulty signal transduction via the Ras pathway plays a key role in tumorigenesis. In this work, a non-radioactive assay was used to quantify Ras activity in hematologic malignancies. Ras activation was measured in six different cell lines and 24 patient samples, and sequence analysis of N- and K-ras was performed. The 24 patient samples comprised of seven acute myelogenous leukemia (AML) samples, five acute lymphocytic leukemia (ALL) samples, four myeloproliferative disease (MPD) samples, four lymphoma samples, four juvenile myelomonocytic leukemia (JMML) samples, and WBC from a healthy donor. The purpose of this study was to compare Ras activity determined by percentage of Ras-GTP with the mutational status of the Ras gene in the hematopoietic cells of the patients. Mutation analysis revealed ras mutations in two of the seven AML samples, one in codon 12 and one in codon 61; ras mutations were also found in two of the four JMML samples, and in one of the four lymphoma samples (codon 12). We found a mean Ras activation of 23.1% in cell lines with known constitutively activating ras mutations, which was significantly different from cell lines with ras wildtype sequence (Ras activation of 4.8%). Two of the five activating ras mutations in the patient samples correlated with increased Ras activation. In the other three samples, Ras was probably activated through "upstream" or "downstream" mechanisms.

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Figures

Fig. 1
Fig. 1
Ras Activation in 12 different determinations (dots) of Ras activation [GTP/(GDT+GTP)%] of control cells lines according to their mutational status. Samples with known WT sequences are shown separate from samples with known activating mutation. The 95% CI are shown by bars. Average ras activation in WT versus mutation samples is 4.75% (0.8–8.7%) vs. 23.06% (12.7–38%) respectively. This difference is significant (p = 0.006; t-test, ungrouped)
Fig. 2
Fig. 2
Ras activation of patient samples according to their mutational status. Numbers in bold represent average levels of Ras activation. A patient sample was considered to have activated Ras if activation level was within the 95% confidence interval (CI) of the positive controls, and negative for Ras activation if it was within the 95% CI of the negative controls. The 95% CIs of the positive and negative controls are represented by vertical bars

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