HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies

被引：6

作者：

Bobrowicz, Malgorzata ^{[1
,2
]}

Dwojak, Michal ^{[1
,2
]}

Pyrzynska, Beata ^{[1
]}

Stachura, Joanna ^{[1
,2
]}

Muchowicz, Angelika ^{[1
]}

Berthel, Elise ^{[3
]}

Dalla-Venezia, Nicole ^{[3
]}

Kozikowski, Mieszko ^{[1
,4
]}

Siernicka, Marta ^{[1
,2
]}

Miazek, Nina ^{[1
]}

Zapala, Piotr ^{[1
]}

Domagala, Antoni ^{[1
]}

Bojarczuk, Kamil ^{[1
]}

Malenda, Agata ^{[5
]}

Barankiewicz, Joanna ^{[6
]}

Graczyk-Jarzynka, Agnieszka ^{[1
]}

Zagozdzon, Agnieszka ^{[1
]}

Gabrysiak, Magdalena ^{[1
]}

Diaz, Jean-Jacques ^{[3
]}

Karp, Marta ^{[7
]}

Lech-Maranda, Ewa ^{[5
,6
]}

Firczuk, Malgorzata ^{[1
]}

Giannopoulos, Krzysztof ^{[7
,8
]}

Efremov, Dimitar G. ^{[9
]}

Laurenti, Luca ^{[10
]}

Baatout, Dunja ^{[11
,12
]}

Frenzel, Lukas ^{[11
,12
]}

Malinowska, Agata ^{[13
]}

Slabicki, Mikolaj ^{[14
,15
,16
]}

Zenz, Thorsten ^{[14
,15
,16
,17
]}

Zerrouqi, Abdessamad ^{[1
]}

Golab, Jakub ^{[1
,18
]}

Winiarska, Magdalena ^{[1
]}

机构：

[1] Med Univ Warsaw, Sch Mol Med, Dept Immunol, Warsaw, Poland

[2] Med Univ Warsaw, Sch Mol Med, Postgrad Sch Mol Med, Warsaw, Poland

[3] CNRS, UMR5286, INSERM U1052, Ctr Leon Berard,Ctr Rech Cancerol Lyon, Lyon, France

[4] European Hlth Ctr, Dept Urol, Ctr Postgrad Med Educ, Otwock, Poland

[5] Inst Hematol & Transfus Med, Warsaw, Poland

[6] Ctr Postgrad Med Educ, Dept Hematol & Transfus Med, Warsaw, Poland

[7] St Johns Canc Ctr Lublin, Dept Hematol, Lublin, Poland

[8] Med Univ Lublin, Dept Expt Hematol, Lublin, Poland

[9] Int Ctr Genet Engn & Biotechnol, Mol Hematol, Trieste, Italy

[10] Catholic Univ Hosp A Gemelli, Dept Hematol, Rome, Italy

[11] Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany

[12] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany

[13] Polish Acad Sci, Inst Biochem & Biophys, Mass Spectrometry Lab, Warsaw, Poland

[14] Natl Ctr Tumor Dis NCT Heidelberg, Mol Therapy Hematol & Oncol, Heidelberg, Germany

[15] Natl Ctr Tumor Dis NCT Heidelberg, Dept Translat Oncol, Heidelberg, Germany

[16] German Canc Res Ctr, Heidelberg, Germany

[17] Univ Hosp Heidelberg, Dept Med 5, Heidelberg, Germany

[18] Med Univ Warsaw, Ctr Preclin Res & Technol, Warsaw, Poland

来源：

BLOOD | 2017年 / 130卷 / 14期

基金：

欧盟第七框架计划;

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL LYMPHOMA; HISTONE DEACETYLASE INHIBITORS; NON-HODGKIN-LYMPHOMA; MULTIPLE-MYELOMA; ANTITUMOR-ACTIVITY; CANCER-THERAPY; RITUXIMAB RESISTANCE; AGGRESOME FORMATION; DOWN-REGULATION;

D O I：

10.1182/blood-2016-08736066

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1628 / 1638

页数：11

共 57 条

[1] Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor ACY-1215 and Bortezomib Is Synergistic in Lymphoma [J].