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      ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3 ITD


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          Bromodomain‐containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/β‐catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/β‐catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal effects in treating AML. Here, we found that co‐treatment with ACC010 and HHT synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in FMS‐like tyrosine kinase 3‐internal tandem duplication ( FLT3‐ITD)–positive AML cells in vitro, and significantly inhibiting AML progression in vivo. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, when HHT was added, ACC010‐resistant cells demonstrated a good synergy. We also extended our study to the mouse BaF3 cell line with FLT3‐inhibitor‐resistant FLT3‐ITD/tyrosine kinase domain mutations and AML cells without FLT3‐ITD. Collectively, our results suggested that the combination treatment of ACC010 and HHT might be a promising strategy for AML patients, especially those carrying FLT3‐ITD.


          Co‐treatment with a novel BRD4 inhibitor (ACC010) and homoharringtonine (HHT) synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in AML with FLT3‐ITD mutation. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, HHT could enhance the efficacy of the BRD4 inhibitor to help overcome resistance by targeting MYC and WNT/β‐catenin pathway.

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          Cancer statistics, 2012.

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,638,910 new cancer cases and 577,190 deaths from cancer are projected to occur in the United States in 2012. During the most recent 5 years for which there are data (2004-2008), overall cancer incidence rates declined slightly in men (by 0.6% per year) and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.6% per year in women. Over the past 10 years of available data (1999-2008), cancer death rates have declined by more than 1% per year in men and women of every racial/ethnic group with the exception of American Indians/Alaska Natives, among whom rates have remained stable. The most rapid declines in death rates occurred among African American and Hispanic men (2.4% and 2.3% per year, respectively). Death rates continue to decline for all 4 major cancer sites (lung, colorectum, breast, and prostate), with lung cancer accounting for almost 40% of the total decline in men and breast cancer accounting for 34% of the total decline in women. The reduction in overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 1,024,400 deaths from cancer. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those groups in the lowest socioeconomic bracket. Copyright © 2012 American Cancer Society, Inc.
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            Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia.

            Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts.
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              RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.

              Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.

                Author and article information

                Mol Oncol
                Mol Oncol
                Molecular Oncology
                John Wiley and Sons Inc. (Hoboken )
                21 January 2023
                July 2023
                : 17
                : 7 ( doiID: 10.1002/mol2.v17.7 )
                : 1402-1418
                [ 1 ] Department of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou China
                [ 2 ] Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy Zhejiang University Hangzhou China
                [ 3 ] Zhejiang Provincial Clinical Research Center for Hematological Disorders Hangzhou China
                [ 4 ] Zhejiang University Cancer Center Hangzhou China
                [ 5 ] The Affiliated People's Hospital of Ningbo University China
                [ 6 ] Jinan Microecological Biomedicine Shandong Laboratory China
                Author notes
                [*] [* ] Correspondence

                J. Jin, Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, #79 Qingchun Rd, Hangzhou, Zhejiang 310003, China

                Fax/Tel: +86 571 87236702

                E‐mail: jiej0503@ 123456zju.edu.cn

                Author information
                MOL213368 MOLONC-22-0565.R1
                © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 06 November 2022
                : 21 July 2022
                : 23 December 2022
                Page count
                Figures: 8, Tables: 0, Pages: 1418, Words: 9069
                Funded by: Key International Cooperation Projects of the National Natural Science Foundation of China
                Award ID: 81820108004
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 82170144
                Acute Myeloid Leukemia
                Research Article
                Research Articles
                Custom metadata
                July 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.1 mode:remove_FC converted:06.07.2023

                Oncology & Radiotherapy
                acute myeloid leukemia, flt3‐itd,homoharringtonine,novel brd4 inhibitor acc010


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