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Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma

2020; Elsevier BV; Volume: 4; Issue: 22 Linguagem: Inglês

10.1182/bloodadvances.2020002566

2473-9537

Tiziana Bruno, Francesca De Nicola, Giacomo Corleone, Valeria Catena, Frauke Goeman, Matteo Pallocca, Cristina Sorino, Gianluca Bossi, Bruno Amadio, Giovanni Cigliana, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Enrico P. Spugnini, Alfonso Baldi, Mario Cioce, Giancarlo Cortese, Elisabetta Mattei, Roberta Merola, Umberto Gianelli, Luca Baldini, Francesco Pisani, Svitlana Gumenyuk, Andrea Mengarelli, Katja Höpker, Thomas Benzing, Bruno Vincenzi, Aristide Floridi, Claudio Passananti, Giovanni Blandino, Simona Iezzi, Maurizio Fanciulli,

Histone Deacetylase Inhibitors Research

Abstract 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.