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DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells

by Bouhya, Salahedine , Bruyer, Angelique , Hose, Dirk , Seckinger, Anja , Vincent, Laure , Herviou, Laurie , Veyrune, Jean-luc , Nicolas, Robert , Goldschmidt, Hartmut , Maes, Ken , Cartron, Guillaume , Müller-Tidow, Carsten , Vanderkerken, Karin , Rème, Thierry , Requirand, Guilhem , Boireau, Stéphanie , Moreaux, Jerome , De Bruyne, Elke , Kassambara, Alboukadel , Klein, Bernard

in Blood cancer / Clinical trials / Epigenetics / Gene expression / Interferon regulatory factor 4 / Malignancy / Maturation / Multiple myeloma / Myc protein / Patients / Plasma cells / Risk groups / Therapeutic applications / Tumor cell lines

2018

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DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells

2018

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DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells

2018

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Journal Article

DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells

Bouhya, Salahedine,

Bruyer, Angelique,

Hose, Dirk,

Seckinger, Anja,

Vincent, Laure,

Herviou, Laurie,

Veyrune, Jean-luc,

Nicolas, Robert,

Goldschmidt, Hartmut,

Maes, Ken,

Cartron, Guillaume,

Müller-Tidow, Carsten,

Vanderkerken, Karin,

Rème, Thierry,

Requirand, Guilhem,

Boireau, Stéphanie,

Moreaux, Jerome,

De Bruyne, Elke,

Kassambara, Alboukadel,

Klein, Bernard

2018

Overview

BackgroundMultiple myeloma (MM) is the second most common hematologic malignancy. Aberrant epigenetic modifications have been reported in MM and could be promising therapeutic targets. As response rates are overall limited but deep responses occur, it is important to identify those patients who could indeed benefit from epigenetic-targeted therapy.MethodsSince HDACi and DNMTi combination have potential therapeutic value in MM, we aimed to build a GEP-based score that could be useful to design future epigenetic-targeted combination trials. In addition, we investigated the changes in GEP upon HDACi/DNMTi treatment.ResultsWe report a new gene expression-based score to predict MM cell sensitivity to the combination of DNMTi/HDACi. A high Combo score in MM patients identified a group with a worse overall survival but a higher sensitivity of their MM cells to DNMTi/HDACi therapy compared to a low Combo score. In addition, treatment with DNMTi/HDACi downregulated IRF4 and MYC expression and appeared to induce a mature BMPC plasma cell gene expression profile in myeloma cell lines.ConclusionIn conclusion, we developed a score for the prediction of primary MM cell sensitivity to DNMTi/HDACi and found that this combination could be beneficial in high-risk patients by targeting proliferation and inducing maturation.

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Publisher

Nature Publishing Group

Subject

/ Interferon regulatory factor 4

/ Malignancy

/ Maturation