Pericole Fernando Vieira, Lazarini Mariana, de Paiva Luciana Bueno, Duarte Adriana da Silva Santos, Vieira Ferro Karla Priscila, Niemann Fernanda Soares, Roversi Fernanda Marconi, Olalla Saad Sara Teresinha
Hematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, Brazil.
Department of Pharmaceutical Sciences, Federal University of São Paulo, São Paulo, Brazil.
Front Oncol. 2019 Jan 29;9:16. doi: 10.3389/fonc.2019.00016. eCollection 2019.
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell-based disorders characterized by ineffective hematopoiesis, increased genomic instability and a tendency to progress toward acute myeloid leukemia (AML). MDS and AML cells present genetic and epigenetic abnormalities and, due to the heterogeneity of these molecular alterations, the current treatment options remain unsatisfactory. Hypomethylating agents (HMA), especially azacitidine, are the mainstay of treatment for high-risk MDS patients and HMA are used in treating elderly AML. The aim of this study was to investigate the potential role of the epigenetic reader bromodomain-containing protein-4 (BRD4) in MDS and AML patients. We identified the upregulation of the short variant BRD4 in MDS and AML patients, which was associated with a worse outcome of MDS. Furthermore, the inhibition of BRD4 with JQ1 or shRNA induced leukemia cell apoptosis, especially when combined to azacitidine, and triggered the activation of the DNA damage response pathway. JQ1 and AZD6738 (a specific ATR inhibitor) also synergized to induce apoptosis in leukemia cells. Our results indicate that the BRD4-dependent transcriptional program is a defective pathway in MDS and AML pathogenesis and its inhibition induces apoptosis of leukemia cells, which is enhanced in combination with HMA or an ATR inhibitor.
骨髓增生异常综合征（MDS）是以无效造血、基因组不稳定性增加以及有向急性髓系白血病（AML）进展趋势为特征的基于克隆造血干细胞的疾病。MDS和AML细胞存在遗传和表观遗传异常，并且由于这些分子改变的异质性，目前的治疗选择仍然不尽人意。去甲基化药物（HMA），尤其是阿扎胞苷，是高危MDS患者的主要治疗药物，HMA也用于治疗老年AML患者。本研究的目的是调查表观遗传阅读器含溴结构域蛋白4（BRD4）在MDS和AML患者中的潜在作用。我们发现MDS和AML患者中短变体BRD4上调，这与MDS较差的预后相关。此外，用JQ1或短发夹RNA抑制BRD4可诱导白血病细胞凋亡，尤其是与阿扎胞苷联合使用时，并触发DNA损伤反应途径的激活。JQ1和AZD6738（一种特异性ATR抑制剂）也协同诱导白血病细胞凋亡。我们的结果表明，依赖BRD4的转录程序是MDS和AML发病机制中的一条缺陷途径，其抑制可诱导白血病细胞凋亡，与HMA或ATR抑制剂联合使用时这种作用会增强。
