Arsenic Trioxide as an Inducer of Apoptosis and Loss of PML/RARα Protein in Acute Promyelocytic Leukemia Cells
Wenlin Shao,Mirco Fanelli,Felicetto Ferrara,R. Riccioni,Angelika Rosenauer,Kelly Davison,William W. Lamph,Samuel Waxman,P. G. Pelicci,F Lo Coco,Giuseppe Avvisati,Ugo Testa,Cesare Peschle,Carlo Gambacorti-Passerini,Clara Nervi,Wilson H. Miller +15 more
TLDR
The molecular basis of these differences in the effects of As2O3 and retinoic acid may guide the clinical use of arsenic compounds and provide insights into the management of leukemias that do not respond to retinic acid.Abstract:
Background: Retinoids, which are derivatives of vitamin A, induce differentiation of acute promyelocytic leukemia (APL) cells in vitro and in patients. However, APL cells develop resistance to retinoic acid treatment. Arsenic trioxide (As2O3) can induce clinical remission in patients with APL, including those who have relapsed after retinoic acid treatment, by inducing apoptosis (programmed cell death) of the leukemia cells. In this study, we investigated the molecular mechanisms by which As2O3 induces apoptosis in retinoic acid-sensitive NB4 APL cells, in retinoic acid-resistant derivatives of these cells, and in fresh leukemia cells from patients. Methods: Apoptosis was assessed by means of DNA fragmentation analyses, TUNEL assays (i.e., deoxyuridine triphosphate labeling of DNA nicks with terminal deoxynucleotidyl transferase), and flow cytometry. Expression of the PML/RARa fusion protein in leukemia cells was assessed by means of western blotting, ligand binding, and immunohistochemistry. Northern blotting and ribonuclease protection assays were used to evaluate changes in gene expression in response to retinoic acid and As 2 O 3 treatment. Results and Conclusions: As2O3 induces apoptosis without differentiation in retinoic acid-sensitive and retinoic acidresistant APL cells at concentrations that are achievable in patients. As 2 O 3 induces loss of the PML/RARa fusion protein in NB4 cells, in retinoic-acid resistant cells derived from them, in fresh APL cells from patients, and in non-APL cells transfected to express this protein. As2O3 and retinoic acid induce different patterns of gene regulation, and they inhibit the phenotypes induced by each other. Understanding the molecular basis of these differences in the effects of As 2O3 and retinoic acid may guide the clinical use of arsenic compounds and provide insights into the management of leukemias that do not respond to retinoic acid. [J Natl Cancer Inst 1998;90:124‐33]read more
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Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide
Steven L. Soignet,Peter Maslak,Zhugang Wang,Suresh C. Jhanwar,Elizabeth Calleja,Laura J. Dardashti,Diane Corso,Anthony DeBlasio,Janice Gabrilove,David A. Scheinberg,Pier Paolo Pandolfi,Raymond P. Warrell +11 more
TL;DR: Low doses of arsenic trioxide can induce complete remissions in patients with APL who have relapsed and the clinical response is associated with incomplete cytodifferentiation and the induction of apoptosis with caspase activation in leukemic cells.
Journal ArticleDOI
Retinoic acid and arsenic trioxide for acute promyelocytic leukemia
Francesco Lo-Coco,Giuseppe Avvisati,Marco Vignetti,Christian Thiede,Simona Iacobelli,Felicetto Ferrara,Paola Fazi,Laura Cicconi,E. Di Bona,Giorgina Specchia,Simona Sica,Mariadomenica Divona,Alessandro Levis,Walter Fiedler,Elisa Cerqui,Massimo Breccia,Giuseppe Fioritoni,Mario Cazzola,L. Melillo,Enrica Morra,Bernd Hertenstein,Mohammed Wattad,Michael Lübbert,Mathias Hänel,Norbert Schmitz,Alessandro Rambaldi,G. La Nasa,Mario Luppi,Fabio Ciceri,Olimpia Finizio,Adriano Venditti,Francesco Fabbiano,Konstanze Döhner,M. Sauer,Arnold Ganser,Sergio Amadori,Franco Mandelli,Hartmut Döhner,Gerhard Ehninger +38 more
TL;DR: ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL.
Journal ArticleDOI
Deconstructing a Disease: RAR, Its Fusion Partners, and Their Roles in the Pathogenesis of Acute Promyelocytic Leukemia
Ari Melnick,Jonathan D. Licht +1 more
TL;DR: The elucidation of the molecular basis of acute promyelocytic leukemia emerged as a paradigm for the connection between the bench and bedside and it became apparent that APL was, among the forms of acute myeloid leukemia, uniquely sensitive to all
Journal Article
Mechanisms of action of arsenic trioxide.
TL;DR: Substantial data show that arsenic trioxide produces remissions in patients with APL at least in part through a mechanism that results in the degradation of the aberrant PML-retinoic acid receptor alpha fusion protein.
Journal ArticleDOI
RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation.
Michael H. Tatham,Marie-Claude Geoffroy,Linnan Shen,Anna Plechanovová,Neil Hattersley,Ellis Jaffray,Jorma J. Palvimo,Ronald T. Hay +7 more
TL;DR: It is demonstrated that poly-SUMO chains can act as discrete signals from mono-SumOylation, in this case targeting a poly- SUMOylated substrate for ubiquitin-mediated proteolysis.
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Zhi-Xiang Shen,Guo-Qiang Chen,Jian-Hua Ni,Xiu-Shong Li,Shu-Min Xiong,Qian-Yao Qiu,Jun Zhu,Wei Tang,Guan-Lin Sun,Kan-Qi Yang,Yu Chen,Li Zhou,Zhi-Wen Fang,Yan-Ting Wang,Jun Ma,Peng Zhang,Ting-Dong Zhang,Sai-Juan Chen,Zhu Chen,Zhen-Yi Wang +19 more
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The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR
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