Myc 增强子簇调节正常和白血病造血干细胞层次,Nature

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Myc 增强子簇调节正常和白血病造血干细胞层次
Nature ( IF 50.5 ) Pub Date : 2018-01-17 , DOI: 10.1038/nature25193
Carsten Bahr , Lisa von Paleske , Veli V. Uslu , Silvia Remeseiro , Naoya Takayama , Stanley W. Ng , Alex Murison , Katja Langenfeld , Massimo Petretich , Roberta Scognamiglio , Petra Zeisberger , Amelie S. Benk , Ido Amit , Peter W. Zandstra , Mathieu Lupien , John E. Dick , Andreas Trumpp , François Spitz

转录因子 Myc 对造血干细胞和祖细胞的调节至关重要，并且在造血系统恶性肿瘤中具有关键作用。在这里，我们展示了位于 Myc 基因下游 1.7 兆碱基处的一个进化保守区域，该区域以前被标记为“超级增强子”对于调节小鼠和人类正常造血和白血病干细胞层次结构中的 Myc 表达水平至关重要. 小鼠中该区域的缺失导致造血干细胞和祖细胞中 Myc 表达的完全丧失。这导致了分化停滞的多能祖细胞的积累以及骨髓和 B 细胞的丢失，模拟了造血干细胞中由 Mx1-Cre 介导的 Myc 基因条件性缺失引起的表型。这种超级增强子包含多个具有选择性活性的增强子模块，可招募转录因子纲要，包括 GFI1b、RUNX1 和 MYB。对携带单个增强子模块缺失的小鼠的分析表明，在大多数造血层级中，特定的 Myc 表达水平受单个增强子模块的组合和累加活性控制，这些模块共同作为“血液增强子簇”（BENC）发挥作用。我们表明 BENC 对于维持小鼠 MLL-AF9 驱动的白血病也是必不可少的。此外，控制小鼠造血干细胞和祖细胞中 Myc 表达的 BENC 模块显示，与原始细胞相比，人类急性髓系白血病干细胞的染色质可及性增加。这种差异与 MYC 表达和患者结果相关。

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A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies

The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a ‘super-enhancer’ is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors. This caused an accumulation of differentiation-arrested multipotent progenitors and loss of myeloid and B cells, mimicking the phenotype caused by Mx1-Cre-mediated conditional deletion of the Myc gene in haematopoietic stem cells. This super-enhancer comprises multiple enhancer modules with selective activity that recruits a compendium of transcription factors, including GFI1b, RUNX1 and MYB. Analysis of mice carrying deletions of individual enhancer modules suggests that specific Myc expression levels throughout most of the haematopoietic hierarchy are controlled by the combinatorial and additive activity of individual enhancer modules, which collectively function as a ‘blood enhancer cluster’ (BENC). We show that BENC is also essential for the maintenance of MLL–AF9-driven leukaemia in mice. Furthermore, a BENC module, which controls Myc expression in mouse haematopoietic stem cells and progenitors, shows increased chromatin accessibility in human acute myeloid leukaemia stem cells compared to blasts. This difference correlates with MYC expression and patient outcome. We propose that clusters of enhancers, such as BENC, form highly combinatorial systems that allow precise control of gene expression across normal cellular hierarchies and which also can be hijacked in malignancies.

更新日期：2018-01-17

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