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Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia

Nature volume 391, pages 815–818 (1998)Cite this article

Abstract

The transforming proteins of acute promyelocytic leukaemias (APL) are fusions of the promyelocytic leukaemia (PML) and the promyelocytic leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-α (RARα)1,2. These proteins retain the RARα DNA- and retinoic acid (RA)-binding domains, and their ability to block haematopoietic differentiation depends on the RARα DNA-binding domain3,4,5,6. Thus RA-target genes are downstream effectors7,8. However, treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML–RARα APLs, whereas PLZF–RARα APLs are resistant to RA1,2. Transcriptional regulation by RARs involves modifications of chromatin by histone deacetylases, which are recruited to RA-target genes by nuclear co-repressors9,10. Here we show that both PML–RARα and PLZF–RARα fusion proteins recruit the nuclear co-repressor (N-CoR)–histone deacetylase complex through the RARα CoR box. PLZF–RARα contains a second, RA-resistant binding site in the PLZF amino-terminal region. High doses of RA release histone deacetylase activity from PML–RARα, but not from PLZF–RARα. Mutation of the N-CoR binding site abolishes the ability of PML–RARα to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biological effects of PLZF–RARα from being an inhibitor to an activator of the RA signalling pathway. Therefore, recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of RA on the stability of the PML–RARα and PLZF–RARα co-repressor complexes determines the differential response of APLs to RA.

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Figure 1: Interactions of PML–RARα and PLZF–RARα with N-CoR and histone deacetylase.
Figure 2: Effects of PML–RARα AHT on differentiation.
Figure 3: Differential N-CoR–fusion protein interactions.
Figure 4: Effects of TSA on RA-induced TGase expression and differentiation of U937 PML–RARα or PLZF–RARα cells.
Figure 5: A model for the interactions of APL fusion proteins with the N-CoR–mSin3–histone deacetylase (HD) complex.

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Acknowledgements

We thank P. P. DiFiore, K. Ozato, K. Helin, T. Casini and M. Maccarana for discussions, and C. Matteucci, S. DiPietro and S. Lupo for technical help. S.D.M., V.G. and M.F. are recipients of fellowships from A.U.L.L., A.I.R.C. and INT (Milan), respectively.

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Authors and Affiliations

  1. Istituto di Medicina Interna e Scienze Oncologiche, Perugia University, 06100, Perugia, Italy

    Francesco Grignani, Silvia De Matteis, Vania Gelmetti, Fausto Grignani & Pier Giuseppe Pelicci

  2. Department of Haematology and Oncology, Istituto Superiore di Sanità, 00161, Rome, Italy

    Francesco Grignani

  3. Dipartimento di Istologia ed Embriologia Medica, University of Rome La Sapienza, 00161, Rome, Italy

    Clara Nervi & Fabiana F. Ferrara

  4. Department of Experimental Oncology, European Institute of Oncology, 20141, Milan, Italy

    Lucia Tomassoni, Mario Cioce, Mirco Fanelli, Saverio Minucci & Pier Giuseppe Pelicci

  5. Division of Endocrinology, Department of Medicine and Department of Genetics, Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Marthin Ruthardt

  6. Institute of Molecular Biology, Unviersity of Vienna, Vienna Biocenter, Vienna, Austria

    Iris Zamir & Mitchell A. Lazar

  7. Department of Haematology, Johann Wolfgang Goethe-University, Frankfurt, Germany

    Christian Seiser

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  1. Francesco Grignani
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Correspondence to Pier Giuseppe Pelicci.

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Grignani, F., De Matteis, S., Nervi, C. et al. Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia. Nature 391, 815–818 (1998). https://doi.org/10.1038/35901

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