In vivo treatment with epigenetic modulating agents induces transcriptional alterations associated with prognosis and immunomodulation in multiple myeloma

• Verfasst von: Maes, Ken [VerfasserIn]
• Verfasst von: Hose, Dirk [VerfasserIn]
• Verfasst von: Seckinger, Anja [VerfasserIn]
• Titel: In vivo treatment with epigenetic modulating agents induces transcriptional alterations associated with prognosis and immunomodulation in multiple myeloma
• Verf.angabe: Ken Maes, Eva De Smedt, Alboukadel Kassambara, Dirk Hose, Anja Seckinger, Els Van Valckenborgh, Eline Menu, Bernard Klein, Karin Vanderkerken, Jérôme Moreaux and Elke De Bruyne
• Jahr: 2015
• Umfang: 16 S.
• Fussnoten: Published online: December 26, 2014 ; Gesehen am 19.07.2017
• Titel Quelle: Enthalten in: OncoTarget
• Ort Quelle: [Erscheinungsort nicht ermittelbar] : Impact Journals LLC, 2010
• Jahr Quelle: 2015
• Band/Heft Quelle: 6(2015), 5, Seite 3319-3334
• ISSN Quelle: 1949-2553
• DOI: doi:10.18632/oncotarget.3207
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1561019712

Abstract

Histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) are in early clinical development for multiple myeloma (MM) therapy. Despite all encouraging pre-clinical data, clinical activity of HDACi and DNMTi is mostly lacking. To optimize the trials, characterization of the in vivo response towards HDACi and DNMTi will be crucial. Therefore, we investigated the transcriptional response after in vivo treatment with the HDACi quisinostat or DNMTi decitabine using the murine 5T33MM model., We identified 504 and 154 genes deregulated by quisinostat and decitabine, respectively. Of interest, MM patients' gene expression levels of 62 quisinostat- and 25 decitabine-deregulated genes were predictive for overall survival of patients. This prognostic information was implemented in a DNA methylation and histone acetylation score. A high score was related to a high proliferative and immature phenotype of MM cells. Furthermore, highly scored MM patients had an adverse overall survival. Interestingly, bio-informatic prediction tools revealed an association of quisinostat-deregulated genes with lymphocyte activation, proliferation, immune-effector mechanisms and T-helper-1 development., Overall, treatment of 5T33MM mice with epigenetic modulating agents led to the translation of gene signatures to predict overall survival of MM patients. HDACi mainly deregulated tumoral immunomodulatory pathways, supporting the rationale to combine HDACi with immunomodulatory therapies.