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
- PMID: 18784923
- PMCID: PMC2755762
- DOI: 10.1007/s00277-008-0593-6
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
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.
Figures


Similar articles
-
Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network.Nat Genet. 2015 Nov;47(11):1334-40. doi: 10.1038/ng.3420. Epub 2015 Oct 12. Nat Genet. 2015. PMID: 26457648
-
Somatic mutations activating Wiskott-Aldrich syndrome protein concomitant with RAS pathway mutations in juvenile myelomonocytic leukemia patients.Hum Mutat. 2018 Apr;39(4):579-587. doi: 10.1002/humu.23399. Epub 2018 Jan 19. Hum Mutat. 2018. PMID: 29316027
-
Detection of N-RAS and K-RAS in their active GTP-bound form in acute myeloid leukemia without activating RAS mutations.Leuk Lymphoma. 2006 Jul;47(7):1387-91. doi: 10.1080/10428190600565925. Leuk Lymphoma. 2006. PMID: 16923573
-
RAS pathway mutations in juvenile myelomonocytic leukemia.Acta Haematol. 2008;119(4):207-11. doi: 10.1159/000140632. Epub 2008 Jun 20. Acta Haematol. 2008. PMID: 18566538 Review.
-
Oncogenes in myeloproliferative disorders.Cell Cycle. 2007 Mar 1;6(5):550-66. doi: 10.4161/cc.6.5.3919. Epub 2007 Mar 24. Cell Cycle. 2007. PMID: 17351342 Review.
Cited by
-
Diabetic retinopathy, superoxide damage and antioxidants.Curr Pharm Biotechnol. 2011 Mar 1;12(3):352-61. doi: 10.2174/138920111794480507. Curr Pharm Biotechnol. 2011. PMID: 20939803 Free PMC article. Review.
-
Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.Nature. 2024 May;629(8013):927-936. doi: 10.1038/s41586-024-07379-z. Epub 2024 Apr 8. Nature. 2024. PMID: 38588697 Free PMC article.
References
-
- {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1073/pnas.81.13.4008', 'is_inner': False, 'url': 'https://doi.org/10.1073/pnas.81.13.4008'}, {'type': 'PMC', 'value': 'PMC345357', 'is_inner': False, 'url': 'https://pmc.ncbi.nlm.nih.gov/articles/PMC345357/'}, {'type': 'PubMed', 'value': '6330729', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/6330729/'}]}
- Fasano O, Aldrich T et al (1984) Analysis of the transforming potential of the human H-ras gene by random mutagenesis. Proc Natl Acad Sci U S A 81(13):4008–4012. doi:10.1073/pnas.81.13.4008 - PMC - PubMed
-
- {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '10374400', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/10374400/'}]}
- Guo W, Tang B et al (1998) N-ras mutations in 43 Chinese cases of acute myeloid leukemia. Chin Med J (Engl) 111:343–345 - PubMed
-
- {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1111/j.1365-2141.1991.tb08578.x', 'is_inner': False, 'url': 'https://doi.org/10.1111/j.1365-2141.1991.tb08578.x'}, {'type': 'PubMed', 'value': '2012756', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/2012756/'}]}
- Farr C, Gill R et al (1991) Analysis of ras gene mutations in childhood myeloid leukaemia. Br J Haematol 77:323–327. doi:10.1111/j.1365-2141.1991.tb08578.x - PubMed
-
- {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1038/sj.leu.2403274', 'is_inner': False, 'url': 'https://doi.org/10.1038/sj.leu.2403274'}, {'type': 'PubMed', 'value': '14737077', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/14737077/'}]}
- Shih LY, Huang CF et al (2004) Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia 18:466–475. doi:10.1038/sj.leu.2403274 - PubMed
-
- {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1038/sj.leu.2401044', 'is_inner': False, 'url': 'https://doi.org/10.1038/sj.leu.2401044'}, {'type': 'PubMed', 'value': '9639416', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/9639416/'}]}
- Padua RA, Guinn BA et al (1998) RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia 12:887–892. doi:10.1038/sj.leu.2401044 - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Miscellaneous