Role of the histone deacetylase complex in acute promyelocytic leukaemia

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Mutant forms of RARα, created by chromosomal translocations with either the PML (for promyelocytic leukaemia)6,7,8 or the PLZF (for promyelocytic leukaemia zinc finger)9,10 locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML–RARα APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF–RARα patients respond very poorly, if at all11. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. 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data-track-component="article body"> <article lang="en"> <div class="c-article-header"> <header> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Letter</li> <li class="c-article-identifiers__item">Published: <time datetime="1998-02-19">19 February 1998</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Role of the histone deacetylase complex in acute promyelocytic leukaemia</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Richard_J_-Lin-Aff1-Aff2-Aff3" data-author-popup="auth-Richard_J_-Lin-Aff1-Aff2-Aff3" data-author-search="Lin, Richard J.">Richard J. Lin</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Laszlo-Nagy-Aff1-Aff2" data-author-popup="auth-Laszlo-Nagy-Aff1-Aff2" data-author-search="Nagy, Laszlo">Laszlo Nagy</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Satoshi-Inoue-Aff2" data-author-popup="auth-Satoshi-Inoue-Aff2" data-author-search="Inoue, Satoshi">Satoshi Inoue</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Wenlin-Shao-Aff4" data-author-popup="auth-Wenlin-Shao-Aff4" data-author-search="Shao, Wenlin">Wenlin Shao</a><sup class="u-js-hide"><a href="#Aff4">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Wilson_H_-Miller-Aff4" data-author-popup="auth-Wilson_H_-Miller-Aff4" data-author-search="Miller, Wilson H.">Wilson H. Miller Jr</a><sup class="u-js-hide"><a href="#Aff4">4</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 6 authors for this article" title="Show all 6 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Ronald_M_-Evans-Aff1-Aff2" data-author-popup="auth-Ronald_M_-Evans-Aff1-Aff2" data-author-search="Evans, Ronald M." data-corresp-id="c1">Ronald M. Evans<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 391</b>, <span class="u-visually-hidden">pages </span>811–814 (<span data-test="article-publication-year">1998</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">1886 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">962 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">9 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/35895/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Alland, L. et al. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature 387, 49–55 (1997)." href="/articles/35895#ref-CR1" id="ref-link-section-d3420778e362">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Heinzel, T. et al. Acomplex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387, 43–48 (1997)." href="/articles/35895#ref-CR2" id="ref-link-section-d3420778e365">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Nagy, L. et al. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89, 373–380 (1997)." href="/articles/35895#ref-CR3" id="ref-link-section-d3420778e368">3</a></sup> through a class of silencing mediators termed SMRT or N-CoR<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Chen, J. D. & Evans, R. M. Atranscriptional co-repressor that interacts with nuclear hormone receptors. Nature 377, 454–457 (1995)." href="/articles/35895#ref-CR4" id="ref-link-section-d3420778e372">4</a></sup>,<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Horlein, A. J. et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377, 397–404 (1995)." href="/articles/35895#ref-CR5" id="ref-link-section-d3420778e376">5</a></sup>. Mutant forms of RARα, created by chromosomal translocations with either the PML (for promyelocytic leukaemia)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Kakizuka, A. et al. Chromosomal translocation t(15; 17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66, 663–674 (1991)." href="/articles/35895#ref-CR6" id="ref-link-section-d3420778e380">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="de Thé, H. et al. The PML-RARα fusion mRNA generated by the t(15; 17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66, 675–684 (1991)." href="/articles/35895#ref-CR7" id="ref-link-section-d3420778e383">7</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Kastner, P. et al. Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): Structural similarities with a new family of oncoproteins. EMBO J. 11, 629–642 (1992)." href="/articles/35895#ref-CR8" id="ref-link-section-d3420778e386">8</a></sup> or the PLZF (for promyelocytic leukaemia zinc finger)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Chen, Z. et al. Fusion between a novel Krüppel-like zinc finger and the retinoid acid receptor-α locus due to a variant t(11; 17) translocation associated with acute promyelocytic leukemia. EMBO J. 12, 1161–1167 (1993)." href="/articles/35895#ref-CR9" id="ref-link-section-d3420778e390">9</a></sup>,<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Chen, Z. et al. PLZF-RARα fusion proteins generated from the variant t(11; 17) (q23; q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild type retinoid acid receptors. Proc. Natl Acad. Sci. USA 91, 1178–1182 (1994)." href="/articles/35895#ref-CR10" id="ref-link-section-d3420778e395">10</a></sup> locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML–RARα APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF–RARα patients respond very poorly, if at all<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Licht, J. D. et al. Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11; 17). Blood 85, 1083–1094 (1995)." href="/articles/35895#ref-CR11" id="ref-link-section-d3420778e399">11</a></sup>. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.</p></div></div></section> <div class="js-context-bar-sticky-point-mobile" data-track-context="article body"> <div class="c-nature-box c-nature-box--side c-nature-box--access-to-pdf" data-component="entitlement-box" data-test="entitlement-box"> <div class="js-access-button"> <a href="https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2F35895" class="c-article__button" data-test="ra21"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"><use href="#icon-institution"></use></svg> <span class="c-article__button-text">Access through your institution</span> </a> </div> <div class="js-buy-button" data-test="entitlement-box-buy-button"> <a href="#access-options" class="c-article__button 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Chen, S.-J. Chen and S. Schreiber for critical reagents; P. Dhordain for suggestions and comments; H. Y. Kao, J. Schwabe and H. Chen for constructs and reagents; H. Juguilon and J. Alvarez for technical assistance; L. Ong and E. Stevens for administrative assistance; and members of the Evans laboratory for critical reading of the manuscript. R.J.L. is a predoctoral fellow of the Lucille P. Markey Charitable Trust. S.I. acknowledges support from the Uehara Memorial Foundation and the TOYOBO Foundation. R.M.E. is an investigator and L.N. is a research associate of the Howard Hughes Medical Institute at the Salk Institute. W.H.M. is a scholar of the Medical Research Council of Canada. This work was supported by the Howard Hughes Medical Institute and the NIH.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Howard Hughes Medical Institute, La Jolla, 92037, California, USA</p><p class="c-article-author-affiliation__authors-list">Richard J. Lin, Laszlo Nagy & Ronald M. Evans</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">The Salk Institute for Biological Studies, La Jolla, 92037, California, USA</p><p class="c-article-author-affiliation__authors-list">Richard J. Lin, Laszlo Nagy, Satoshi Inoue & Ronald M. Evans</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Graduate Program in Molecular Pathology, University of California San Diego, School of Medicine, La Jolla, 92093, California, USA</p><p class="c-article-author-affiliation__authors-list">Richard J. Lin</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">McGill University Departments of Oncology and Medicine, Lady Davis Institute for Medical Research, Montreal, H3T 1E2, Quebec, Canada</p><p class="c-article-author-affiliation__authors-list">Wenlin Shao & Wilson H. 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Role of the histone deacetylase complex in acute promyelocytic leukaemia | Nature