In vivo treatment with epigenetic modulating agents induces transcriptional alterations associated with prognosis and immunomodulation in multiple myeloma
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Ken Maes1, Eva De Smedt1, Alboukadel Kassambara2,3, Dirk Hose4, Anja Seckinger4, Els Van Valckenborgh1, Eline Menu1, Bernard Klein2,3,5, Karin Vanderkerken1, Jérôme Moreaux2,3,5,* and Elke De Bruyne1,*
1 Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels
2 Department of Biological Haematology, CHU Montpellier, Montpellier, France
3 Institute of Human Genetics, CNRS-UPR1142, Montpellier F-34396, France
4 Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany
5 University of Montpellier 1, UFR de Médecine, Montpellier, France
* These authors contributed equally to this work
Elke De Bruyne, email:
Keywords: Epigenetics, Multiple Myeloma, HDACi, DNMTi, murine model
Received: October 13, 2014 Accepted: December 17, 2014 Published: December 26, 2014
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.
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