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The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-11-14 , DOI: 10.1016/j.ccell.2019.10.004 Yun Huang 1 , Brice Mouttet 1 , Hans-Jörg Warnatz 2 , Thomas Risch 2 , Fabian Rietmann 1 , Fabian Frommelt 3 , Quy A Ngo 1 , Maria Pamela Dobay 1 , Blerim Marovca 1 , Silvia Jenni 1 , Yi-Chien Tsai 1 , Sören Matzk 2 , Vyacheslav Amstislavskiy 2 , Martin Schrappe 4 , Martin Stanulla 5 , Matthias Gstaiger 3 , Beat Bornhauser 1 , Marie-Laure Yaspo 2 , Jean-Pierre Bourquin 1
Cancer Cell ( IF 48.8 ) Pub Date : 2019-11-14 , DOI: 10.1016/j.ccell.2019.10.004 Yun Huang 1 , Brice Mouttet 1 , Hans-Jörg Warnatz 2 , Thomas Risch 2 , Fabian Rietmann 1 , Fabian Frommelt 3 , Quy A Ngo 1 , Maria Pamela Dobay 1 , Blerim Marovca 1 , Silvia Jenni 1 , Yi-Chien Tsai 1 , Sören Matzk 2 , Vyacheslav Amstislavskiy 2 , Martin Schrappe 4 , Martin Stanulla 5 , Matthias Gstaiger 3 , Beat Bornhauser 1 , Marie-Laure Yaspo 2 , Jean-Pierre Bourquin 1
Affiliation
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The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblastic leukemia subtype. Here we decipher the regulome of endogenous TCF3-HLF and dissect its essential transcriptional components and targets by functional genomics. We demonstrate that TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineage associated (super-) enhancers to drive lineage identity and self-renewal. Among direct targets, hijacking an HLF binding site in a MYC enhancer cluster by TCF3-HLF activates a conserved MYC-driven transformation program crucial for leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG and recruits histone acetyltransferase p300 (EP300), conferring susceptibility to EP300 inhibition. Our study provides a framework for targeting driving transcriptional dependencies in this fatal leukemia.
中文翻译：
致白血病的TCF3-HLF复合线增强剂可驱动细胞身份和自我更新，从而赋予EP300脆弱性。
嵌合转录因子TCF3-HLF定义了一种不可治愈的急性淋巴细胞白血病亚型。在这里，我们破译内源性TCF3-HLF的规则，并通过功能基因组学解剖其必需的转录成分和靶标。我们证明，TCF3-HLF在造血干细胞/骨髓谱系相关的（超级）增强子上招募HLF结合位点，以驱动谱系身份和自我更新。在直接靶标中，通过TCF3-HLF劫持MYC增强子簇中的HLF结合位点可激活保守的MYC驱动的转化程序，这对于体内白血病的传播至关重要。TCF3-HLF率先与ERG合作，并募集了组蛋白乙酰转移酶p300（EP300），使人们对EP300的抑制作用敏感。我们的研究为在这种致命性白血病中靶向驱动转录依赖性提供了框架。
更新日期：2019-11-14
中文翻译：
致白血病的TCF3-HLF复合线增强剂可驱动细胞身份和自我更新，从而赋予EP300脆弱性。
嵌合转录因子TCF3-HLF定义了一种不可治愈的急性淋巴细胞白血病亚型。在这里，我们破译内源性TCF3-HLF的规则，并通过功能基因组学解剖其必需的转录成分和靶标。我们证明，TCF3-HLF在造血干细胞/骨髓谱系相关的（超级）增强子上招募HLF结合位点，以驱动谱系身份和自我更新。在直接靶标中，通过TCF3-HLF劫持MYC增强子簇中的HLF结合位点可激活保守的MYC驱动的转化程序，这对于体内白血病的传播至关重要。TCF3-HLF率先与ERG合作，并募集了组蛋白乙酰转移酶p300（EP300），使人们对EP300的抑制作用敏感。我们的研究为在这种致命性白血病中靶向驱动转录依赖性提供了框架。
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