Targeting the T-Cell Lymphoma Epigenome Induces Cell Death, Cancer Testes Antigens, Immune-Modulatory Signaling Pathways.
Targeting the T-Cell Lymphoma Epigenome Induces Cell Death, Cancer Testes Antigens, Immune-Modulatory Signaling Pathways.
复制标题
DOI：
10.1158/1535-7163.mct-20-0377
复制
发表时间：
2021-08
影响因子：
5.7
通讯作者：
O'Connor OA
中科院分区：
文献类型：
--
作者：
Scotto L;Kinahan C;Douglass E;Deng C;Safari M;Casadei B;Marchi E;Lue JK;Montanari F;Falchi L;Qiao C;Renu N;Bates SE;Califano A;O'Connor OA
外周T细胞淋巴瘤(PTCL)可被认为是典型的表观遗传病。作为一种疾病，它们对组蛋白脱乙酰酶(HDAC)和DNA甲基转移酶(DNMT)抑制剂特别敏感，无论是单独还是联合使用，都具有表观遗传基因的大量突变，并可以在基因工程小鼠模型中自发发展，该模型基于已建立的(RHOAG17V)和TET2(控制DNA甲基化的表观遗传基因)的反复突变。鉴于HDAC抑制剂(HDACi)和低甲基化药物在PTCL中单独和联合应用的临床益处，我们试图探索这些药物在PTCL中的机制基础。在这里，我们揭示了在PTCL中HDAC和DNMT抑制剂之间深刻的类别协同作用，并且联合诱导的基因表达程度与单独观察到的药物相比有本质的不同和更广泛的程度。这一组合的一个显著特征与癌症、睾丸抗原和参与免疫反应的基因的转录诱导有关。有趣的是，Tbx21和STAT4，Tbx21和STAT4，是TH1分化的主要调节者，是组合上调的基因之一，表明诱导了TH1样表型。此外，还发现了与胆固醇代谢相关的基因抑制和母体。我们相信，这些数据为临床研究和未来利用免疫表观遗传学平台的组合提供了强有力的理论基础。
The peripheral T-cell lymphomas (PTCL) could be considered the prototypical epigenetic disease. As a disease, they are uniquely sensitive to histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors, both alone and in combination, are characterized by a host of mutations in epigenetic genes, and can develop spontaneously in genetically engineered murine models predicated on established recurring mutations in (RHOAG17V) and TET2, an epigenetic gene governing DNA methylation. Given the clinical benefit of HDAC inhibitors (HDACi) and hypomethlyation agents alone and in combination in PTCL, we sought to explore a mechanistic basis for these agents in PTCL. Herein, we reveal profound class synergy between HDAC and DNMT inhibitors in PTCL, and that the combination induces degrees of gene expression that are substantially different and more extensive than that observed for the single agents. A prominent signature of the combination relates to the transcriptional induction of cancer testis antigens and genes involved in the immune response. Interestingly, TBX21 and STAT4, master regulators of TH1 differentiation, were among the genes upregulated by the combination, suggesting the induction of a TH1-like phenotype. Moreover, suppression of genes involved in cholesterol metabolism and the matrisome were also identified. We believe that these data provide a strong rationale for clinical studies, and future combinations leveraging an immunoepigenetic platform.