Cancers frequently co-opt lineage-specific transcription factors (TFs) utilized in normal development to sustain proliferation. However, the effects of these TFs on tumor development depend considerably on where in the genome they bind. A new paper by Taylor and colleagues expands on previously developed diamidine compounds that obstruct the DNA binding sites of the pioneer TF PU.1 (SPI1) in acute myeloid leukemia (AML). Immobilization and sequencing of genomic DNA targeted by these compounds revealed that these inhibitors alter the genomic binding patterns of PU.1. The authors report that their strategy constrains the genomic binding preferences of PU.1, leading to redistribution of PU.1 to promoters and other gene-proximal regions with elevated G/C content. Here we discuss recent developments for targeting PU.1 in hematologic malignancies. We also explore the shared functional roles of PU.1 and SWI/SNF ATP-dependent chromatin remodeling complexes, which work together to sustain the enhancer landscape needed for tumor cell proliferation but also have key roles in non-tumor settings.

中文翻译：

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先锋转录因子的药理学阻断


癌症经常利用正常发育中使用的谱系特异性转录因子 （TF） 来维持增殖。然而，这些 TF 对肿瘤发展的影响在很大程度上取决于它们在基因组中结合的位置。Taylor 及其同事的一篇新论文扩展了先前开发的二脒化合物，这些化合物会阻碍急性髓性白血病 （AML） 中先驱 TF PU.1 （SPI1） 的 DNA 结合位点。对这些化合物靶向的基因组 DNA 进行固定和测序后发现，这些抑制剂会改变 PU.1 的基因组结合模式。作者报告说，他们的策略限制了 PU.1 的基因组结合偏好，导致 PU.1 重新分布到 G/C 含量升高的启动子和其他基因近端区域。在这里，我们讨论了在血液系统恶性肿瘤中靶向 PU.1 的最新进展。我们还探讨了 PU.1 和 SWI/SNF ATP 依赖性染色质重塑复合物的共同功能作用，它们共同作用以维持肿瘤细胞增殖所需的增强子景观，但在非肿瘤环境中也起关键作用。