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

Francesco Grignani, Silvia De Matteis, Clara Nervi, Lucia Tomassoni, Vania Gelmetti, Mario Cioce, Mirco Fanelli, Marthin Ruthardt, Fabiana F. Ferrara, Iris Zamir, Christian Seiser, Fausto Grignani, Mitchell A. Lazar, Saverio Minucci () and Pier Giuseppe Pelicci ()
Additional contact information
Francesco Grignani: Istituto di Medicina Interna e Scienze Oncologiche, Perugia University
Silvia De Matteis: Istituto di Medicina Interna e Scienze Oncologiche, Perugia University
Clara Nervi: University of Rome La Sapienza
Lucia Tomassoni: European Institute of Oncology
Vania Gelmetti: Istituto di Medicina Interna e Scienze Oncologiche, Perugia University
Mario Cioce: European Institute of Oncology
Mirco Fanelli: European Institute of Oncology
Marthin Ruthardt: Diabetes and Metabolism, University of Pennsylvania School of Medicine
Fabiana F. Ferrara: University of Rome La Sapienza
Iris Zamir: Institute of Molecular Biology, Unviersity of Vienna
Christian Seiser: Johann Wolfgang Goethe-University
Fausto Grignani: Istituto di Medicina Interna e Scienze Oncologiche, Perugia University
Mitchell A. Lazar: Institute of Molecular Biology, Unviersity of Vienna
Saverio Minucci: European Institute of Oncology
Pier Giuseppe Pelicci: Istituto di Medicina Interna e Scienze Oncologiche, Perugia University

Nature, 1998, vol. 391, issue 6669, 815-818

Abstract: 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.

Date: 1998
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DOI: 10.1038/35901

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