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    05-552 Magdalenka, Polska

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ARTHUR ZYGMUNT ZELENT, PH.D.

ARTHUR ZYGMUNT ZELENT, PH.D.

Position: Associate Professor, Institute of Genetics and Animal Breeding the Polish Academy of Sciences

Subject area: Biochemistry, Genetics and Molecular Biology, Medicine, Health Sciences, Chemistry Immunology and Microbiology, Neuroscience Agricultural and Biological, Toxicology and Pharmaceutics

Author details:

Professor Zelent is the author of over 200 publications, of which 116 published in international peer-reviewed journals.

He has published in Nature (IF = 43.070), Science (IF = 36.610), Nature Medicine (IF = 30,641), Nature Genetics (IF = 25,455) or Cancer Cell (IF = 23,916).

The total number of citations to his works is 9868, and the index H = 51 according to the Scopus database.

Most Relevant Examples of my Contributions to Science

As a graduate student I have characterized Hepatitis B Virus transcripts and developed a cell line producing an infectious Hepatitis B virus. Such cell lines were essential for further studies of HBV biology and the development of a vaccine.

  1. Zelent AZ, Sells MA, Price PM, Mohamad A, Acs G and Christman JK. Murine cells carrying integrated tandem genomes of hepatitis B virus DNA transcribe RNAs from endogenous promoters on both viral stands and express middle and major viral envelope proteins. J Virol 1987, 61:1108-1115. (Contribution 80%)
  2. Zelent AZ, Sells MA, Shvartzman M, Price PM and Acs G. Replicative intermediate of hepatitis B virus in transfected murine fibroblasts. J Virol 1987, 61:2921-2923. (Contribution 80%)

During my post-doctoral years in Pierre Chambon’s laboratory I have discovered the Retinoic Acid Receptor gamma and have characterized various retinoic acid isoforms. These findings help in understanding the pleiotropic nature of their ligand mediated function.

  1. Zelent A, Krust A, Petkovich M, Kastner P and Chambon P. Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Nature 1989, 339:714-717. (Contribution 80%)
  2. Zelent A, Mendelsohm C, Kastner P, Krust A, Garnier J-M, Ruffenach F, Leroy P and Chambon P. Differentially expressed isoforms of the mouse retinoic acid receptor-beta are generated by usage of two promoters and alternative splicing. EMBO J 1991, 10:71-81. (Contribution 80%)

After becoming independent scientist I have identified a variant translocation that characterized small fraction of acute promyelocytic leukemia. This translocation involved the same regions of the retinoic acid receptor alpha as the most common variant (PML/RARa) but at the 5-terminus receptor was fused to a newly discovered zinc-finger gene PLZF. In contrast to PML/RARa APL with PLZF/RARa was not sensitive to retinoic acid.

  1. Chen, Z, Brand NJ, Chen A, Chen S-J, Tong J-H, Wang Z-Y, Waxman S, Zelent A. Fusion between a novel Krüppel-like zinc finger gene and the retinoic acid receptor-a locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J 1993, 12:1161-1167. (Contribution 80%)

I also discovered the mechanism underlying this lack of responsiveness of PLZF/RARa, contrasting with PML/RARa, to retinoic acid. The underlying mechanism was that PLZF was a prototypical transcriptional repressor, which through its N-terminal POZ domain interacted with identical co-repressor complex as unliganded receptor. In contrast to the receptor, however, these interactions were not ligand sensitive. Interestingly we demonstrated that PMLfusion to RARa rendered it only less responsive to retinoic acid those higher, pharmacological levels of ligand werfe required to restore it’s function.

  1. He L-Z, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, Pandolfi PP. Distinct interactions of PML-RARa with transcriptional co-repressors determine differential responses to retinoic acid in APL. Nat Genet 1998, 18:126-135. (Contribution 10%)
  2. Guidez F, Ivins S, Zhu J, Söderstöm, Waxman S, Zelent A. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to the PML- and PLZF-RARa underlie molecular pathogenesis and treatment of acute promyelocytic leukaemia. Blood 1998, 91:2634-2642. (Contribution 80%)

I have discovered histone deacytylase one and proposed (tested currently) that it contributes to the pathogenesis of Non-Hodgkins Lymphoma. These results provided a frame work for further studies of protein acetylation in NHL and potential development of inhibitors for clinical trials.

8.         Petrie K, Guidez F, Howell L, Healy L, Waxman S, Greaves M, Zelent A. The histone deacetylase 9 gene encodes multiple protein I      soforms. J Biol Chem 2003, 278: 16059 – 16072. (Contribution 80%)

After large number of years of investigating, as to why aside of APL other AML subtypes don’t respond to retinoic acid, I have discovered that inhibition of LSD1 histone H3 lys4 demethylae (mono- and di-) facilitates retinoic acid response in non-APL AML. This study thus has identified LSD1 as a therapeutic target in AML and possibly many other cancers.

9.   Schenk T, Howell L, Göllner S, Woster P, Marton L, Casero Jr R, Dick J, Mills K, Burnett A, Müller-Tidow C, Petrie K and Zelent A. Inhibition of the LSD1/KDM1 histone demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med 2012, 18:605-611. (Contribution 80%)

Examples of Funded Research

  • Currently I hold the OPUS17 Grant for over 2,3 million PLN
  • Leukemia Lymphoma Society SCOR, Interventional Epigenetics in Hematopoietic Malignancies, $5,000,000 (2017-2022)
  • Unlocking the Therapeutic Potential of Retinoic Acid in AML, $275,000 (2016-2018)
  • Leukaemia Lymphoma Research Specialist Programme Grant, Unlocking the Therapeutic Potential of Retinoic Acid in Treatment of AML, £1,400,000 – Three Post-docs & One Technician (2012-2017)

Patents

  • Transcription therapy for cancer. US patent number 6,262,116 B1, July 17, 2001. Assignee: Sloan-Kettering Institute for Cancer Research; Inventors: Pier Paolo Pandolfi, Raymond P. Warrell, Jr., and Arthur Zelent.
  • Histone deacetylase 9. US patent number 7,291,492 B2. Nov. 6, 2007. Assignee: The Institute of Cancer Research (GB); Inventors: Arthur Zelent, Kevin Petrie, and Fabien Guidez.

Latest publications:

  1. Kahl M, Brioli A, Bens M, Perner F, Kresinsky A, Schnetzke U, Hinze A, Sbirkov Y, Stengel S, Simonetti G, Martinelli G, Petrie K,Zelent A, Böhmer FD, Groth M, Ernst T, Heidel FH, Scholl S, Hochhaus A, Schenk T. The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML. Leukemia. 2019, 33(11):2628-2639
  2. Swords RT, Azzam D, Al-Ali H, Lohse I, Volmar CH, Watts JM, Perez A, Rodriguez A, Vargas F, Elias R, Vega F, Zelent A, Brothers SP, Abbasi T, Trent J, Rangwala S, Deutsch Y, Conneally E, Drusbosky L, Cogle CR, Wahlestedt C. Ex-vivo sensitivity profiling to guide clinical decision making in acute myeloid leukemia: A pilot study. Leuk Res. 2017 Nov 11;64:34-41.
  3. Watts JM, Perez A, Pereira L, Fan YS, Brown G, Vega F, Petrie K, Swords RT, Zelent A. A Case of AML Characterized by a Novel t(4;15)(q31;q22) Translocation That Confers a Growth-Stimulatory Response to Retinoid-Based Therapy. Int J Mol Sci. 2017 Jul 11;18(7).
  4. Sbirkov Y, Kwok C, Bhamra A, Thompson AJ, Gil V, Zelent A, Petrie K. Semi-Quantitative Mass Spectrometry in AML Cells Identifies New Non-Genomic Targets of the EZH2 Methyltransferase. Int J Mol Sci. 2017 Jul 5;18(7).
  5. .Göllner S, Oellerich T, Agrawal-Singh S, Schenk T, Klein HU, Rohde C, Pabst C, Sauer T, Lerdrup M, Tavor S, Stölzel F, Herold S, Ehninger G, Köhler G, Pan KT, Urlaub H, Serve H, Dugas M, Spiekermann K, Vick B, Jeremias I, Berdel WE, Hansen K, Zelent A, Wickenhauser C, Müller LP, Thiede C, Müller-Tidow C. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nat Med. 2017 Jan;23(1):69-78.

Links to professional profiles

Researchgate:  https://www.researchgate.net/profile/Arthur_Zelent

Scopus:  https://www.scopus.com/authid/detail.uri?authorId=7006566218

Collaboration: 

http://www.epigenetic.us/ 

Dr. Arthur Zelent, Leukaemia Research Fund Center, London, England: Dr. Zelent is a team leader at the largest cancer center in Europe. He's been working to identify gene defects and testing compound substances that might trigger self-correction. Dr. Zelent's team discovered why the use of retinoic acid induces differentiation (self-correction) of acute promyelocytic leukemia (APL) cells.