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Leukemia translocation protein PLZF inhibits cell growth and expression of cyclin A

Oncogene volume 18, pages 925–934 (1999)Cite this article

Abstract

The PLZF gene was identified by its fusion with the RARα locus in a therapy resistant form of acute promyelocytic leukemia (APL) associated with the t(11;17)(q23;q21) translocation. Here we describe PLZF as a negative regulator of cell cycle progression ultimately leading to growth suppression. PLZF can bind and repress the cyclin A2 promoter while expression of cyclin A2 reverts the growth suppressed phenotype of myeloid cells expressing PLZF. In contrast RARα-PLZF, a fusion protein generated in t(11;17)(q23;q21)-APL activates cyclin A2 transcription and allows expression of cyclin A in anchorage-deprived NIH3T3 cells. Therefore, cyclin A2 is a candidate target gene for PLZF and inhibition of cyclin A expression may contribute to the growth suppressive properties of PLZF. Deregulation of cyclin A2 by RARα-PLZF may represent an oncogenic mechanism of this chimeric protein and contribute to the aggressive clinical phenotype of t(11;17)(q23;q21)-associated APL.

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Acknowledgements

We thank B Henglein, C Brechot and J Sobczak-Thepot for the cyclin A2 promoter constructs and fruitful discussions, JS Kang and RS Krauss for the cyclin-containing retroviral producer cell lines and M Serrano, N Hastie and J Caceres for careful reading of the manuscript. This work was supported by grants from the National Institutes of Health CA59936 (JDL, SW and AZ), CA62275 (ED) and the American Cancer Society grant DHP 116 (JDL). JDL is a Scholar of the Leukemia Society of America. PLY was supported by the Lauri Strauss Leukemia Fund. RS was supported by a Medical Scientist Training Grant GM0707280-17 from the NIH. KN-B was supported by National Research Service Award CA61646. HJB was supported by the Leukemia Research Foundation. This is publication #250 from the Brookdale Center for Developmental and Molecular Biology.

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Authors and Affiliations

  1. Derald H Ruttenberg Cancer Center, One Gustave L Levy Place, New York, 10029, NY, USA

    Sima Boterashvili, Helen J Ball & Jonathan D Licht

  2. Brookdale Center for Developmental and Molecular Biology, One Gustave L Levy Place, New York, 10029, NY, USA

    Patricia L Yeyati, Rita Shaknovich, Sima Boterashvili, Jia Li, Helen J Ball & Jonathan D Licht

  3. Department of Medicine, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, 10029, NY, USA

    Samuel Waxman & Jonathan D Licht

  4. Leukemia Research Fund Centre, Institute of Cancer Research, London, SW3 6JB, UK

    Arthur Zelent

  5. Laboratory of Molecular Medicine, Memorial Sloan Kettering Cancer Center, New York, 10021, NY, USA

    Kathryn Nason-Burchenal & Ethan Dmitrovsky

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  1. Patricia L Yeyati
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Yeyati, P., Shaknovich, R., Boterashvili, S. et al. Leukemia translocation protein PLZF inhibits cell growth and expression of cyclin A. Oncogene 18, 925–934 (1999). https://doi.org/10.1038/sj.onc.1202375

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