Bobrowicz, Malgorzata ORCID: 0000-0002-9078-5168, Dwojak, Michal, Pyrzynska, Beata ORCID: 0000-0002-0490-618X, Stachura, Joanna, Muchowicz, Angelika ORCID: 0000-0003-4707-1722, Berthel, Elise, Dalla-Venezia, Nicole, Kozikowski, Mieszko, Siernicka, Marta, Miazek, Nina, Zapala, Piotr, Domagala, Antoni, Bojarczuk, Kamil ORCID: 0000-0002-6110-4060, Malenda, Agata ORCID: 0000-0002-3444-2718, Barankiewicz, Joanna ORCID: 0000-0002-5029-9173, Graczyk-Jarzynka, Agnieszka ORCID: 0000-0001-7980-0542, Zagozdzon, Agnieszka, Gabrysiak, Magdalena, Diaz, Jean-Jacques, Karp, Marta ORCID: 0000-0003-1108-1961, Lech-Maranda, Ewa ORCID: 0000-0001-9592-0851, Firczuk, Malgorzata ORCID: 0000-0002-1719-5233, Giannopoulos, Krzysztof ORCID: 0000-0003-0135-4030, Efremov, Dimitar G., Laurenti, Luca ORCID: 0000-0002-8327-1396, Baatout, Dunja, Frenzel, Lukas, Malinowska, Agata ORCID: 0000-0001-6599-901X, Slabicki, Mikolaj, Zenz, Thorsten, Zerrouqi, Abdessamad ORCID: 0000-0002-2628-473X, Golab, Jakub ORCID: 0000-0002-2830-5100 and Winiarska, Magdalena (2017). HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies. Blood, 130 (14). S. 1628 - 1639. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective histone deacetylase inhibitors (HDACis). Because the use of panHDACis is associated with substantial adverse effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance. In this study, we demonstrate for the first time the role of HDAC6 in the regulation of CD20 levels. We show that inhibition of HDAC6 activity significantly increases CD20 levels in established B-cell tumor cell lines and primary malignant cells. Using pharmacologic and genetic approaches, we confirm that HDAC6 inhibition augments in vitro efficacy of antiCD20 mAbs and improves survival of mice treated with rituximab. Mechanistically, we demonstrate that HDAC6 influences synthesis of CD20 protein independently of the regulation of MS4A1 transcription. We further demonstrate that translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition, as shown by the increase of CD20 mRNA within the polysomal fraction, indicating a new role of HDAC6 in the posttranscriptional mechanism of CD20 regulation. Collectively, our findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bobrowicz, MalgorzataUNSPECIFIEDorcid.org/0000-0002-9078-5168UNSPECIFIED
Dwojak, MichalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pyrzynska, BeataUNSPECIFIEDorcid.org/0000-0002-0490-618XUNSPECIFIED
Stachura, JoannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muchowicz, AngelikaUNSPECIFIEDorcid.org/0000-0003-4707-1722UNSPECIFIED
Berthel, EliseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dalla-Venezia, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kozikowski, MieszkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siernicka, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miazek, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zapala, PiotrUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domagala, AntoniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bojarczuk, KamilUNSPECIFIEDorcid.org/0000-0002-6110-4060UNSPECIFIED
Malenda, AgataUNSPECIFIEDorcid.org/0000-0002-3444-2718UNSPECIFIED
Barankiewicz, JoannaUNSPECIFIEDorcid.org/0000-0002-5029-9173UNSPECIFIED
Graczyk-Jarzynka, AgnieszkaUNSPECIFIEDorcid.org/0000-0001-7980-0542UNSPECIFIED
Zagozdzon, AgnieszkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabrysiak, MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diaz, Jean-JacquesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karp, MartaUNSPECIFIEDorcid.org/0000-0003-1108-1961UNSPECIFIED
Lech-Maranda, EwaUNSPECIFIEDorcid.org/0000-0001-9592-0851UNSPECIFIED
Firczuk, MalgorzataUNSPECIFIEDorcid.org/0000-0002-1719-5233UNSPECIFIED
Giannopoulos, KrzysztofUNSPECIFIEDorcid.org/0000-0003-0135-4030UNSPECIFIED
Efremov, Dimitar G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laurenti, LucaUNSPECIFIEDorcid.org/0000-0002-8327-1396UNSPECIFIED
Baatout, DunjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenzel, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malinowska, AgataUNSPECIFIEDorcid.org/0000-0001-6599-901XUNSPECIFIED
Slabicki, MikolajUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zenz, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zerrouqi, AbdessamadUNSPECIFIEDorcid.org/0000-0002-2628-473XUNSPECIFIED
Golab, JakubUNSPECIFIEDorcid.org/0000-0002-2830-5100UNSPECIFIED
Winiarska, MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-214538
DOI: 10.1182/blood-2016-08736066
Journal or Publication Title: Blood
Volume: 130
Number: 14
Page Range: S. 1628 - 1639
Date: 2017
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL LYMPHOMA; HISTONE DEACETYLASE INHIBITORS; NON-HODGKIN-LYMPHOMA; MULTIPLE-MYELOMA; ANTITUMOR-ACTIVITY; CANCER-THERAPY; RITUXIMAB RESISTANCE; AGGRESOME FORMATION; DOWN-REGULATIONMultiple languages
HematologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21453

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