Kasprzyk Marta Elżbieta, Łosiewski Wojciech, Podralska Marta, Kazimierska Marta, Sura Weronika, Dzikiewicz-Krawczyk Agnieszka
Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland.
Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland.
Eur J Pharmacol. 2021 Nov 5;910:174505. doi: 10.1016/j.ejphar.2021.174505. Epub 2021 Sep 14.
B-cell non-Hodgkin lymphoma (NHL) is among the ten most common malignancies. Survival rates range from very poor to over 90% and highly depend on the stage and subtype. Characteristic features of NHL are recurrent translocations juxtaposing an oncogene (e.g. MYC, BCL2) to the enhancers in the immunoglobulin heavy chain (IGH) locus. Survival and proliferation of many B-cell lymphomas depend on the expression of the translocated oncogene. Thus, targeting IGH enhancers as an anti-lymphoma treatment seems a promising strategy. Recently, a small molecule - 7-[(4-methyl-2-pyridinyl)aminomethyl]-8-quinolinol (compound 30666) was identified to decrease activity of the Eμ enhancer and reduce the expression of translocated oncogenes in multiple myeloma and some NHL cell lines (Dolloff, 2019). Here, we aimed to test the effect of compound 30666 in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) and shed light on its mechanism of action. We report that both IGH-translocation positive NHL cells as well as IGH-translocation negative B cells and non-B cell controls treated with compound 30666 exhibited consistent growth inhibition. A statistically significant increase in cell percentage in sub-G1 phase of cell cycle was observed, suggesting induction of apoptosis. Compound 30666 downregulated MYC levels in BL cell lines and altered IGH enhancer RNA expression. Moreover, a global decrease of H3K27ac and an increase of H3K4me1 was observed upon 30666 treatment, which suggests switching enhancers to a poised or primed state. Altogether, our findings indicate that 30666 inhibitor affects enhancer activity but might not be as specific for IGH enhancers as previously reported.
B细胞非霍奇金淋巴瘤（NHL）是十种最常见的恶性肿瘤之一。生存率从极低到超过90%不等，且高度依赖于疾病分期和亚型。NHL的特征性表现是癌基因（如MYC、BCL2）与免疫球蛋白重链（IGH）基因座中的增强子反复发生易位。许多B细胞淋巴瘤的存活和增殖依赖于易位癌基因的表达。因此，靶向IGH增强子作为一种抗淋巴瘤治疗策略似乎很有前景。最近，一种小分子——7-[(4-甲基-2-吡啶基)氨基甲基]-8-喹啉醇（化合物30666）被发现可降低Eμ增强子的活性，并降低多种骨髓瘤和一些NHL细胞系中易位癌基因的表达（多洛夫，2019年）。在此，我们旨在测试化合物30666对伯基特淋巴瘤（BL）和弥漫性大B细胞淋巴瘤（DLBCL）的影响，并阐明其作用机制。我们报告称，用化合物30666处理的IGH易位阳性NHL细胞以及IGH易位阴性B细胞和非B细胞对照均表现出一致的生长抑制。观察到细胞周期亚G1期的细胞百分比有统计学显著增加，提示诱导了细胞凋亡。化合物30666下调了BL细胞系中的MYC水平，并改变了IGH增强子RNA的表达。此外，在30666处理后观察到H3K27ac总体下降和H3K4me1增加，这表明增强子转变为一种准备就绪或起始状态。总之，我们的研究结果表明，30666抑制剂会影响增强子活性，但可能不像先前报道的那样对IGH增强子具有特异性。
