Hydroxycarbamide (HC, hydroxyurea) is a cytoreductive drug inducing cell cycle blockade. However, emerging evidence suggests that HC plays a role in the modulation of transcription through the activity of transcription factors and DNA methylation. Examining the global mechanism of action of HC in the context of myeloproliferative neoplasms (MPNs), for which HC is the first-line treatment, will provide a better understanding of its molecular effects. To explore the effects of HC genome-wide, transcriptomic analyses were performed on two clinically relevant cell types at different stages of differentiation treated with HC in a murine MPN model. This study was replicated in MPN patients by profiling genome-wide gene expression and DNA methylation using patient blood samples collected longitudinally, before and following HC exposure. The effects of HC on the transcriptome were not only associated with cell cycle interruption but also with hematopoietic functions. Moreover, a group of genes were restored to normal expression levels in murine hematopoietic stem cells (HSCs) following drug treatment, including the master regulator of hematopoiesis, RUNX1. In humans, HC significantly modifies DNA methylation levels in HSCs at several distal regulatory regions, which we show to be associated with SPI1 binding sites and at the SPI1 locus itself. We have identified novel targets of HC that include pivotal transcription factors involved in hematopoiesis, and for the first time we report abnormal methylation patterns in MPN patients at the master regulator gene SPI1 and its distal binding sites, which HC is able to restore to normal levels.

中文翻译：

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羟基脲对骨髓增殖性肿瘤 DNA 甲基化和基因表达的影响

羟基脲（HC，羟基脲）是一种细胞减少药物，可诱导细胞周期阻滞。然而，新出现的证据表明，HC 通过转录因子的活性和 DNA 甲基化在转录调节中发挥作用。在骨髓增生性肿瘤 (MPN) 的背景下检查 HC 的整体作用机制，其中 HC 是一线治疗，将更好地了解其分子效应。为了探索 HC 全基因组的影响，在小鼠 MPN 模型中，对两种不同分化阶段的临床相关细胞类型进行了转录组分析。这项研究通过使用纵向收集的患者血液样本、HC 暴露之前和之后的全基因组基因表达和 DNA 甲基化分析在 MPN 患者中复制。HC 对转录组的影响不仅与细胞周期中断有关，而且与造血功能有关。此外，在药物治疗后，一组基因在小鼠造血干细胞 (HSC) 中恢复到正常表达水平，包括造血主调节因子，运行 1。在人类中，HC 显着改变了几个远端调节区域的 HSC 中的 DNA 甲基化水平，我们证明这与 SPI1 结合位点和SPI1基因座本身有关。我们已经确定了 HC 的新靶点，包括参与造血的关键转录因子，并且我们首次报告了 MPN 患者中主调节基因SPI1及其远端结合位点的异常甲基化模式，HC 能够恢复到正常水平.