TY - JOUR
T1 - Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma
AU - Bruno, Tiziana
AU - de Nicola, Francesca
AU - Corleone, Giacomo
AU - Catena, Valeria
AU - Goeman, Frauke
AU - Pallocca, Matteo
AU - Sorino, Cristina
AU - Bossi, Gianluca
AU - Amadio, Bruno
AU - Cigliana, Giovanni
AU - Ricciardi, Maria Rosaria
AU - Petrucci, Maria Teresa
AU - Spugnini, Enrico Pierluigi
AU - Baldi, Alfonso
AU - Cioce, Mario
AU - Cortese, Giancarlo
AU - Mattei, Elisabetta
AU - Merola, Roberta
AU - Gianelli, Umberto
AU - Baldini, Luca
AU - Pisani, Francesco
AU - Gumenyuk, Svitlana
AU - Mengarelli, Andrea
AU - Höpker, Katja
AU - Benzing, Thomas
AU - Vincenzi, Bruno
AU - Floridi, Aristide
AU - Passananti, Claudio
AU - Blandino, Giovanni
AU - Iezzi, Simona
AU - Fanciulli, Maurizio
N1 - Funding Information:
The authors acknowledge the CINECA award under the ISCRA initiative, for the availability of high-performance computing resources and support (project: IscrC_ROCIMM). This work was supported by the Italian Association for Cancer Research (AIRC) (15255 [M.F.] and 14455 [G. Blandino]). G. Corleone has received funding from AIRC and from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 800924.
Publisher Copyright:
© 2020 by The American Society of Hematology
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/24
Y1 - 2020/11/24
N2 - Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che-1 depletion leads to a reduction of “active chromatin” by inducing a global decrease of histone acetylation. In this context, Che-1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che-1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.
AB - Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che-1 depletion leads to a reduction of “active chromatin” by inducing a global decrease of histone acetylation. In this context, Che-1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che-1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.
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U2 - 10.1182/bloodadvances.2020002566
DO - 10.1182/bloodadvances.2020002566
M3 - Article
C2 - 33186461
AN - SCOPUS:85097226231
VL - 4
SP - 5616
EP - 5630
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 22
ER -