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Myelodysplasias

Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

Leukemia volume 20, pages 635–644 (2006)Cite this article

Abstract

AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with −7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of −5/5q- and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)–RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, P<0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signal-regulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with −7/7q- alteration, and frequently involves RTK–RAS signaling pathway activation.

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Osaka Cancer Research Foundation, and the Tsuchiya Foundation. We are grateful to Ryoko Matsumoto-Yamaguchi for excellent technical support in carrying out these experiments. We also thank Dr Ross Fisher and Dr Hideaki Nakajima for critical reading of the article.

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  1. H Niimi, H Harada and Y Harada: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    H Niimi, H Harada, Y Ding, J Imagawa & A Kimura

  2. International Radiation Information Center, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Y Harada

  3. Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    T Inaba

  4. Department of Internal Medicine, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan

    T Kyo

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Niimi, H., Harada, H., Harada, Y. et al. Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations. Leukemia 20, 635–644 (2006). https://doi.org/10.1038/sj.leu.2404136

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