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

Abstract

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.

Epigenetic treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory effects

“…We have previously shown in human myeloma cell lines that this combination represses MYC transcriptional responses. 17 Similarly, MYC expression was downregulated in the murine 5T33vt cells upon treatment confirming the MYC-targeting effects of combining DNMTi and HDACi in MM (Supplementary Figure S1H). The combination effects were also observed with 100 nM DAC and 10 nM Quis which in the 4-day combination setup resulted in 70% Annexin-V positivity at day 6 and 80% at day 7 (Supplementary Figure S1I).…”

“…In line with the above studies, we observed significant cytotoxic activity and MYC depletion of the combination of DAC and Quis in the murine MM cells in this study and in previous published studies in HMCLs. 17,22 …”

BrdU incorporation in multiparameter flow cytometry: A new cell cycle assessment approach in multiple myeloma

“…The prognostic value of proliferation assessment using BrdU incorporation was analyzed in 60 newly diagnosed patients treated with high dose chemotherapy supported by autologous hematopoietic stem cell transplantation (HSCT). Using R Maxstat algorithm , allowing to determine the optimal cutpoint for continuous variables , we identified that MM patients with a percentage of proliferating MMCs >1.42 are associated with a significant shorter event free survival (20 months median EFS) ( P = 0.0005) compared with patients with a percentage of proliferating MMCs ≤ 1.42 (not reached median EFS) (Fig. B).…”

TAZ functions as a tumor suppressor in multiple myeloma by downregulating MYC

“…Similarly, in both our study ( Figure 6E-H) and others, the combination of DAC with HDAC inhibitors is more efficacious due to the synergistic deregulation of specific cell-survival genes. 65,[71][72][73] Precise mechanisms responsible for this synergy remain to be elucidated and are likely to involve numerous signaling molecules 63,65,71,73,74 and to be cell type dependent. Our model suggests that these antimyeloma therapies upregulate TAZ, leading to decreased MYC expression and its transcriptional program and subsequent cell death.…”