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Leukemogenesis

Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype

Leukemia volume 17, pages 2492–2499 (2003)Cite this article

Abstract

Point mutations of the transcription factor AML1 are associated with leukemogenesis in acute myeloblastic leukemia (AML). Internal tandem duplications (ITDs) in the juxtamembrane domain and mutations in the second tyrosine kinase domain of the Fms-like tyrosine kinase 3 (FLT3) gene represent the most frequent genetic alterations in AML. However, such mutations per se appear to be insufficient for leukemic transformation. To evaluate whether both AML1 and FLT3 mutations contribute to leukemogenesis, we analyzed mutations of these genes in AML M0 subtype in whom AML1 mutations were predominantly observed. Of 51 patients, eight showed a mutation in the Runt domain of the AML1 gene: one heterozygous missense mutation with normal function, five heterozygous frameshift mutations and two biallelic nonsense or frameshift mutations, resulting in haploinsufficiency or complete loss of the AML1 activities. On the other hand, a total of 10 of 49 patients examined had the FLT3 mutation. We detected the FLT3 mutation in five of eight (63%) patients with AML1 mutation, whereas five of 41 (12%) without AML1 mutation showed the FLT3 mutation (P=0.0055). These observations suggest that reduced AML1 activities predispose cells to the acquisition of the activating FLT3 mutation as a secondary event leading to full transformation in AML M0.

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Acknowledgements

The authors are very grateful to Drs M Takeuchi, A Takeshita, K Kawakami, K Isogai and all contributors to this work for their kind help. We thank to Ms H Ogata for technical assistances. This work is supported in part by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science and Culture, Grants-in-Aid for Cancer Research from Japanese Ministry of Health and Welfare (No. 9-2).

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Authors and Affiliations

  1. Department of Internal Medicine II, Kumamoto University School of Medicine, Japan

    N Matsuno, T Nanri, H Mitsuya & N Asou

  2. Institute of Molecular and Cell Biology, National University of Singapore, Singapore

    M Osato, N Yamashita, M Yanagida & Y Ito

  3. Institute for Virus Research, Kyoto University, Japan

    N Yamashita, M Yanagida & K Shigesada

  4. First Department of Internal Medicine, Fukui Medical University, Japan

    T Fukushima

  5. Department of Hematology, Tokyo Women's Medical University, Japan

    T Motoji

  6. First Department of Internal Medicine, Saitama Medical School, Japan

    S Kusumoto

  7. Molecular Medicine, Graduate School of Medicine, Nagoya University, Japan

    M Towatari

  8. Division of Molecular Medicine, Aichi Cancer Center, Japan

    R Suzuki

  9. Department of Infectious Diseases, Nagoya University School of Medicine, Japan

    T Naoe

  10. Second Department of Internal Medicine, Mie University, Japan

    K Nishii

  11. Aichi Cancer Center, Nagoya, Japan

    R Ohno

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Matsuno, N., Osato, M., Yamashita, N. et al. Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype. Leukemia 17, 2492–2499 (2003). https://doi.org/10.1038/sj.leu.2403160

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