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

Ken Maes, Eva De Smedt, Alboukadel Kassambara, D. Hose, Anja Seckinger, Els Van Valckenborgh, Eline Menu, Bernard Klein, Karin Vanderkerken, Elke De Bruyne

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18 Citations (Scopus)


Multiple myeloma (MM) is a hematological malignancy characterized by a plasma cell accumulation in the bone marrow (BM). Pre-clinical research showed that epigenetic modulating agents have promising therapeutic and prognostic applications in MM. Early clinical work however has been disappointing. To provide new possibilities for combinatory therapies, reduce side effects and identify biomarkers, better understanding of the therapeutic and prognostic features of HDACi and DNMTi is needed, especially in vivo where MM cells are protected by the BM microenvironment. Therefore, we aimed to characterize the transcriptional response of MM cells after in vivo treatment with the HDACi quisinostat or the DNMTi decitabine using the syngeneic immunocompetent murine 5T33MM model.
5T33MM mice (n=4/group) with established disease were treated with quisinostat or decitabine for 5 days after which tumor cells were subjected to microarray analysis. Quisinostat or decitabine deregulated respectively 61 and 25 genes with a prognostic value in newly diagnosed patients. The prognostic value of these genes was then implemented in a murine (Mu)-DM and Mu-HA score. The score values were significant higher in MM patients and human myeloma cell lines compared to healthy bone marrow plasma cells. In addition, the scores could separate newly diagnosed as well as relapsed patients into a low risk and high risk group. A high score was furthermore identified in the proliferation subgroup, in patients with a high gene-expression based proliferation index and in immature plasma cell stages. Gene ontology analysis showed that the deregulated genes encoded for proteins involved in apoptosis, regulation of cytoskeleton, immune regulation, metabolism, development and regulation of transcription. Pathway analysis revealed associations with lymphocyte activation and proliferation, immune-effector mechanisms, T-helper-1 development and elevated signaling of interferon, tumor necrosis factor, interleukin-1 (IL-1), IL-2 and IL-12.
In conclusion, the in vivo transcriptional response to epigenetic modulating agents provided a prognostic gene signature and was significantly associated with immune regulation. This provides the rationale for testing epigenetic modulating agents in combination with immunotherapies.
Original languageEnglish
JournalBelgian Journal of Hematology
Publication statusPublished - 31 Jan 2015
Event30th General Annual Meeting of Belgian Hematological Society - La Hulpe, Belgium
Duration: 30 Jan 2015 → …

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