DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells.
DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells.
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DOI：
10.1038/s41416-018-0025-x
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发表时间：
2018-04
影响因子：
8.8
通讯作者：
Moreaux J
中科院分区：
文献类型：
--
作者：
Bruyer A;Maes K;Herviou L;Kassambara A;Seckinger A;Cartron G;Rème T;Robert N;Requirand G;Boireau S;Müller-Tidow C;Veyrune JL;Vincent L;Bouhya S;Goldschmidt H;Vanderkerken K;Hose D;Klein B;De Bruyne E;Moreaux J
多发性骨髓瘤(MM)是第二常见的血液系统恶性肿瘤。异常的表观遗传修饰已在多发性骨髓瘤中被报道，并可能成为有希望的治疗靶点。由于应答率总体上是有限的，但发生了深刻的反应，因此确定哪些患者确实可以从表观遗传学靶向治疗中受益是很重要的。由于HDACi和DNMTi联合治疗多发性骨髓瘤具有潜在的治疗价值，我们的目标是建立一个基于GEP的评分，这可能有助于设计未来的表观遗传学靶向联合试验。此外，我们还研究了HDACi/DNMTi治疗后GEP的变化。我们报告了一种新的基于基因表达的评分来预测MM细胞对DNMTi/HDACi组合的敏感性。MM患者的高COMBO评分表明，与低COMBO评分相比，MM患者的总体存活率较差，但其MM细胞对DNMTi/HDACi治疗的敏感性较高。此外，DNMTi/HDACi治疗下调了骨髓瘤细胞系中IRF4和MYC的表达，并似乎诱导了成熟的BMPC浆细胞基因表达谱。总而言之，我们开发了一种用于预测原代MM细胞对DNMTi/HDACi敏感性的评分，并发现这种组合可能通过靶向增殖和诱导成熟而有益于高危患者。
Multiple 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. Since 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. We 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. In 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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影响因子：
45.3
作者：
Decaux, Olivier;Lode, Laurence;Minvielle, Stephane
通讯作者：
Minvielle, Stephane
影响因子：
--
作者：
Jourdan M;Cren M;Schafer P;Robert N;Duperray C;Vincent L;Ceballos P;Cartron G;Rossi JF;Moreaux J;Chopra R;Klein B
通讯作者：
Klein B
影响因子：
8
作者：
De Vos, J;Thykjær, T;Klein, B
通讯作者：
Klein, B
影响因子：
20.3
作者：
Derenne, S;Monia, B;Amiot, M
通讯作者：
Amiot, M
影响因子：
4.4
作者：
Jourdan, Michel;Caraux, Anouk;Klein, Bernard
通讯作者：
Klein, Bernard