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  • Original Paper
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Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein

Oncogene volume 18, pages 3716–3724 (1999)Cite this article

Abstract

The NPM-MLF1 chimeric protein is produced by the t(3;5)(q25.1;q34) chromosomal translocation, which is associated with myelodysplastic syndrome (MDS) prior to progression into acute myeloid leukemia (AML). Here we report that K562 human leukemia cells ectopically expressing NPM-MLF1, but not those with wild-type MLF1, were gradually eliminated from the culture by undergoing apoptosis. NIH3T3 mouse fibroblasts engineered to overexpress NPM-MLF1 grew normally but serum deprivation triggered apoptotic cell death with slower kinetics than did other well-known apoptotic inducers such as c-Myc or E2F-1. Quantitative analysis of apoptotic induction confirmed that, neither NPM nor MLF1, but the NPM-MLF1 fusion protein was able to induce apoptosis. Analyses using a variety of deletion mutants of NPM-MLF1 revealed that induction of apoptosis required the N-terminal domain of MLF1 and the NPM domain containing nuclear localization signal and that removal of the NPM dimerization domain markedly impaired the ability to induce apoptosis. Co-expression of Bcl-2 rescued NIH3T3 fibroblasts from NPM-MLF1-mediated cell death without affecting the expression level or the subcellular localization of NPM-MLF1 and enabled cells to progress into S phase in low serum. These findings provide an NPM-MLF1-mediated novel mechanism of apoptotic induction and imply that NPM-MLF1 in collaboration with anti-apoptotic oncoproteins may play an important role in multi-step progression from MDS to AML.

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Acknowledgements

We thank Drs K Umesono and J Fujisawa for the plasmids; and Drs SW Morris, J Fujisawa and R Amakawa for critical review of the manuscript. Supported by Grants-in-Aid for Scientific Research and for Cancer Research from the Ministry of Education, Science and Culture of Japan, and by Hayashi Memorial Foundation for Female Natural Scientists.

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Authors and Affiliations

  1. First Department of Internal Medicine, Kansai Medical University, 10-15 Fumisono, Moriguchi, 570-0074, Osaka, Japan

    Noriko Yoneda-Kato & Shirou Fukuhara

  2. Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, 630-0101, Nara, Japan

    Jun-ya Kato

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  1. Noriko Yoneda-Kato
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Yoneda-Kato, N., Fukuhara, S. & Kato, Jy. Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein. Oncogene 18, 3716–3724 (1999). https://doi.org/10.1038/sj.onc.1202711

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