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      The Bromodomain Inhibitor JQ1 Enhances the Responses to All- trans Retinoic Acid in HL-60 and MV4-11 Leukemia Cells

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          Abstract

          All- trans retinoic acid (ATRA) is a highly effective treatment for acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML). However, ATRA-based treatment is not effective in other subtypes of AML. In non-APL AML, ATRA signaling pathway is impaired or downmodulated, and consequently fails to respond to pharmacological doses of ATRA. Therefore, complementary treatment strategies are needed to improve ATRA responsiveness in non-APL AML. In this study, we investigated the combined effect of ATRA and bromodomain inhibitor JQ1, proven to have potent anti-cancer activity mainly through inhibition of c-Myc. We showed that the combination of ATRA with JQ1 synergistically inhibited proliferation of AML cells. The synergistic growth inhibition was resulted from differentiation or apoptosis depending on the kind of AML cells. Concomitantly, the combined treatment of ATRA and JQ1 caused greater depletion of c-Myc and hTERT expression than each agent alone in AML cells. Taken together, these findings support the rationale for the use of the combination of ATRA and JQ1 as a therapeutic strategy for the treatment of AML.

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          A decade of molecular biology of retinoic acid receptors.

          P Chambon (1996)
          Retinoids play an important role in development, differentiation, and homeostasis. The discovery of retinoid receptors belonging to the superfamily of nuclear ligand-activated transcriptional regulators has revolutionized our molecular understanding as to how these structurally simple molecules exert their pleiotropic effects. Diversity in the control of gene expression by retinoid signals is generated through complexity at different levels of the signaling pathway. A major source of diversity originates from the existence of two families of retinoid acid (RA) receptors (R), the RAR isotypes (alpha, beta, and gamma) and the three RXR isotypes (alpha, beta, and gamma), and their numerous isoforms, which bind as RXR/RAR heterodimers to the polymorphic cis-acting response elements of RA target genes. The possibility of cross-modulation (cross-talk) with cell-surface receptors signaling pathways, as well as the finding that RARs and RXRs interact with multiple putative coactivators and/or corepressors, generates additional levels of complexity for the array of combinatorial effects that underlie the pleiotropic effects of retinoids. This review focuses on recent developments, particularly in the area of structure-function relationships.
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            Transcriptional regulation and transformation by Myc proteins.

            Sovana Adhikary, Martin Eilers (2005)
            Myc genes are key regulators of cell proliferation, and their deregulation contributes to the genesis of most human tumours. Recently, a wealth of data has shed new light on the biochemical functions of Myc proteins and on the mechanisms through which they function in cellular transformation.
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              BET inhibitor resistance emerges from leukaemia stem cells.

              Chun Yew Fong, Omer Gilan, Enid Y N Lam … (2015)
              Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/β-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Stem Cells
                Journal ID (iso-abbrev): Int J Stem Cells
                Journal ID (publisher-id): IJSC
                Title: International Journal of Stem Cells
                Publisher: Korean Society for Stem Cell Research
                ISSN (Print): 2005-3606
                ISSN (Electronic): 2005-5447
                Publication date Collection: 2018
                Publication date (Electronic): 30 April 2018
                Volume: 11
                Issue: 1
                Pages: 131-140
                Affiliations
                [1 ]Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Korea
                [2 ]Department of Immunology and Physiology, School of Medicine, Konkuk University, Seoul, Korea
                [3 ]Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju, Korea
                Author notes
                Correspondence to: Hyung-Min Chung, Department of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea, Tel: +82-2-2049-6232, Fax: +82-2-455-9015, E-mail: stemchung@ 123456gmail.com
                Article
                Publisher ID: ijsc-11-131
                DOI: 10.15283/ijsc18021
                PMC ID: 5984067
                PubMed ID: 29699387
                SO-VID: a68ef08f-a258-4c1c-8ab0-81c2a7372605
                Copyright © Copyright © 2018 by the Korean Society for Stem Cell Research
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 06 March 2018
                Date revision received : 23 March 2018
                Date accepted : 23 March 2018
                Categories
                Subject: Original Article

                Keywords: acute myeloid leukemia,all-trans retinoic acid,jq1,c-myc,differentiation,apoptosis
                Data availability:
                Keywords: acute myeloid leukemia, all-trans retinoic acid, jq1, c-myc, differentiation, apoptosis

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