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Entinostat) Restores Expression of Silenced Leukemia-Associated Transcription Factors Nur77 and Nor1 and of Key Pro-Apoptotic Proteins in AML

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Entinostat) Restores Expression of Silenced Leukemia-Associated Transcription Factors Nur77 and Nor1 and of Key Pro-Apoptotic Proteins in AML Leukemia (2013) 27, 1358–1368 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu ORIGINAL ARTICLE HDAC inhibition by SNDX-275 (Entinostat) restores expression of silenced leukemia-associated transcription factors Nur77 and Nor1 and of key pro-apoptotic proteins in AML L Zhou1, VR Ruvolo1, T McQueen1, W Chen1, IJ Samudio1, O Conneely2, M Konopleva1 and M Andreeff1 Nur77 and Nor1 are highly conserved orphan nuclear receptors. We have recently reported that nur77 À / À nor1 À / À mice rapidly develop acute myeloid leukemia (AML) and that Nur77 and Nor1 transcripts were universally downregulated in human AML blasts. These findings indicate that Nur77 and Nor1 function as leukemia suppressors. We further demonstrated silencing of Nur77 and Nor1 in leukemia stem cells (LSCs). We here report that inhibition of histone deacetylase (HDAC) using the specific class I HDAC inhibitor SNDX-275 restored the expression of Nur77/Nor1 and induced expression of activator protein 1 transcription factors c-Jun and JunB, and of death receptor TRAIL, in AML cells and in CD34 þ /38 À AML LSCs. Importantly, SNDX-275 induced extensive apoptosis in AML cells, which could be suppressed by silencing nur77 and nor1. In addition, pro-apoptotic proteins Bim and Noxa were transcriptionally upregulated by SNDX-275 in AML cells and in LSCs. Our present work is the first report of a novel mechanism of HDAC inhibitor-induced apoptosis in AML that involves restoration of the silenced nuclear receptors Nur77 and Nor1, activation of activator protein 1 transcription factors, a death receptor and pro-apoptotic proteins. Leukemia (2013) 27, 1358–1368; doi:10.1038/leu.2012.366 Keywords: SNDX-275; Nur77/Nor1; apoptosis; AML INTRODUCTION This finding suggests that silencing of Nur77 and Nor1 is a critical Acute myeloid leukemia (AML) arises from the clonal expansion of step in the pathogenesis of AML. Nur77 and Nor1 share 90% aberrant myeloid progenitor cells; their increased proliferation and homology in the DNA-binding domain and they can both bind as failure to differentiate results in an accumulation of myeloblasts. monomers to a consensus NGFI-B response element sequence, or Only one-third of younger adult patients diagnosed with AML can as homodimers to Nur-responsive element,14,15 hence sharing a set be cured, whereas older patients experience even lower survival of common target genes. Nur77 has been shown to regulate the rates.1 Although many preclinical and clinical studies have sought induction of Fas-L, TRAIL and pro-opiomelanocortin in lymphocytes to elucidate the biological and molecular basis of AML, the or endocrine cells;16,17 however, the common targets of Nur77 and mechanism of AML pathogenesis remains undefined in the Nor1 are not well characterized. Molecular analysis of nur77 À / À / majority of cases. Recently, we reported that mice deficient in nor1 À / À mice revealed that the absence of both nur77 and nor1 Nur77 and Nor1 develop AML-like disease and that reduced gene was associated with downregulation of the activator protein 1 dosage of Nur77 and Nor1 leads to mixed myelodysplastic/ transcription factors c-Jun and JunB and downregulation of the myeloproliferative neoplasms with progression to AML in rare extrinsic apoptosis inducers TRAIL and Fas-L in myeloid leukemia cases.2,3 Orphan nuclear receptors Nur77 (also termed NR4A1, TR3 cells.2 or NGFI-B) and Nor1 (also termed NR4A3 or MINOR) are highly Epigenetic modifications have been shown to have critical roles conserved members of the nuclear receptor family. As transcription in regulating gene expression.18 Human tumor cells, including factors, they are involved in various physiological and cellular leukemia cells, exhibit a global loss of monoacetylation of histone functions, including apoptosis, mitosis, inflammation and H4, and aberrant histone acetyltransferase (HAT) and/or histone differentiation.4–7 Induction and activation of Nur77 and/or Nor1 deacetylase (HDAC) activity has been shown to be associated with have central roles in negative selection of T lymphocytes, cancer development19–22 and hematological malignancies.23–27 macrophage activation-induced cell death and apoptosis induced HDAC inhibitors display selective antitumor activity by inducing by antineoplastic agents in various cancer cells.5,8–11 Consistent apoptosis, growth arrest and differentiation and induce the with the parallel functions of these transcription factors, mice expression of cell-cycle inhibitors p21, p19 and p57 and of the deficient in either nur77 or nor1 display relatively subtle pro-apoptotic gene TRAIL in leukemia cells.28–31 Notably, two abnormalities,12,13 whereas mice deficient in both genes develop HDAC inhibitors, vorinostat (suberoylanilide hydroxamic acid) and rapidly lethal and transplantable AML.2 Importantly, the expression romidepsin (Istodax) have been approved by the Food and Drug of Nur77 and Nor1 transcripts was profoundly decreased in Administration for clinical treatment of cutaneous T-cell leukemic blasts from all AML patients studied, compared with the lymphoma, and HDAC inhibitors valproic acid, suberoylanilide levels in normal bone marrow cells, regardless of cytogenetics.2 hydroxamic acid and MGCD0103 have shown clinical efficacy 1Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA and 2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Correspondence: Dr M Andreeff, Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. E-mail: [email protected] Received 14 April 2011; revised 2 November 2012; accepted 6 November 2012; accepted article preview online 18 December 2012; advance online publication, 5 February 2013 HDAC inhibitor SNDX-275 induces apoptosis in AML L Zhou et al 1359 in ongoing AML trials.28,32–34 We hypothesized that histone surviving cells ¼ viable cell number in treated sample  100/viable cell acetylation has a role in gene silencing of Nur77/Nor1 and number in control sample. % specific apoptosis ¼ ((% annexin V þ in HDAC inhibitor SNDX-275 was used in our study. SNDX-275 treated sample) À (% annexin V þ in control sample)  100)Ä(100 À (% þ 37 (Entinostat), a synthetic benzamide derivative, selectively inhibits annexin V in control sample)). The number of surviving LSCs from the activities of class I HDACs (HDAC1, 2 and 3),35 has shown primary patient samples was determined using a method described previously.36 % surviving cells ¼ viable CD34 þ /38 À cell number in impressive efficacy in vitro and in vivo against a variety of tumors þ À 35 treated sample  100/viable CD34 /38 cell number in control sample. and is currently in phase I/II clinical trials. CD34 þ /38 À , CD34 þ /38 þ and CD33 þ /34 À cell populations were isolated In this study, we demonstrate that Nur77 and Nor1 are from primary AML samples as previously described.36 profoundly silenced not only in bulk leukemia cells but also in leukemia stem cells (LSCs). This silencing was largely reversed by the HDAC inhibitor SNDX-275 alone or in combination with Gene-expression assay another Nur77/Nor1 inducer ionomycin. The restoration of Nur77/ Total RNA was extracted with Trizol (Invitrogen, Carlsbad, CA, USA) Nor1 by SNDX-275 was accompanied by upregulation of c-Jun, following the manufacturer’s instructions. A total of 500 ng of cDNA was used for each real-time PCR reaction. All Taqman assays for measuring JunB, TRAIL, Bim and Noxa in AML cells and LSCs. This resulted in gene expression were purchased from Applied Biosystems (Foster City, CA, extensive apoptosis of bulk AML and LSCs. USA), and the real-time PCR was conducted and analyzed with the 7900HT Fast Real-Time PCR System (Applied Biosystems). The abundance of each transcript relative to that of Abl1 was calculated as follows: Copies per 100 MATERIALS AND METHODS Abl1 ¼ 100  2 exp [ À DCt], where DCt is the mean Ct of the transcript of Chemicals and cell cultures interest less than the mean Ct of the transcript for Abl1. SNDX-275 (Entinostat) was kindly provided by Dr. Peter Ordentlich (Syndax Pharmaceuticals, Inc., Waltham, MA, USA). Trichostatin A, suberoylanilide hydroxamic acid, depsipeptide (FK228) and ionomycin were purchased Western blotting 6 from Sigma-Aldrich (St Louis, MO, USA), Aton Pharma (Lawrenceville, NY, Lysates of 1  10 cells were loaded onto a 10 or 12% SDS-PAGE gel USA) and Fujisawa Pharmaceutical Co. Ltd (Osaka, Japan), respectively. (Bio-Rad, Hercules, CA, USA) and proteins were transferred to Hybond-P AML cell lines HL-60, MOLM13, OCI-AML3 and OCI-AML2 were purchased membranes (Amersham Pharmacia Biotech, Piscataway, NJ, USA), followed from ATCC (Manassas, VA, USA). Bone marrow or peripheral blood samples by immunoblotting. Signals were detected using a PhosphorImager (Storm were obtained consecutively for in vitro studies from patients diagnosed 860, version 4.0; Molecular Dynamics, Sunnyvale, CA, USA). The following with AML during routine diagnostic workup under informed consent in antibodies were used: mouse monoclonal histone3 (Upstate, Billerica, MA, accordance with regulations and protocols approved by the Institutional USA), rabbit polyclonal histone4 (Upstate), rabbit polyclonal acetyl- Review Board Committee of the University of Texas M. D. Anderson Cancer histone3 (Upstate), rabbit polyclonal acetyl-histone4 (Upstate), rabbit Center. Primary AML samples were harvested
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