title: In vivo treatment with epigenetic modulating agents induces transcriptional alterations associated with prognosis and immunomodulation in multiple myeloma.
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.
authors: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Ken
authors: K
authors: Maes
authors: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Eva
authors: E
authors: De Smedt
authors: Department of Biological Haematology, CHU Montpellier, Montpellier, France.|Institute of Human Genetics, CNRS-UPR1142, Montpellier, France.
authors: Alboukadel
authors: A
authors: Kassambara
authors: Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany.
authors: Dirk
authors: D
authors: Hose
authors: Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany.
authors: Anja
authors: A
authors: Seckinger
authors: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Els
authors: E
authors: Van Valckenborgh
authors: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Eline
authors: E
authors: Menu
authors: Department of Biological Haematology, CHU Montpellier, Montpellier, France.|Institute of Human Genetics, CNRS-UPR1142, Montpellier, France.|University of Montpellier 1, UFR de Médecine, Montpellier, France.
authors: Bernard
authors: B
authors: Klein
authors: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Karin
authors: K
authors: Vanderkerken
authors: Department of Biological Haematology, CHU Montpellier, Montpellier, France.|Institute of Human Genetics, CNRS-UPR1142, Montpellier, France.|University of Montpellier 1, UFR de Médecine, Montpellier, France.
authors: Jérôme
authors: J
authors: Moreaux
authors: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Elke
authors: E
authors: De Bruyne
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019295:Computational Biology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000401:mortality; D014158:Transcription, Genetic / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C541788:quisinostat; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine