2019年11月14日，瑞士苏黎世大学儿童医院Jean-Pierre Bourquin研究组在《癌细胞》杂志在线发表论文。他们的工作表明，引起白血病的TCF3-HLF复合物通过增强子重连实现细胞身份的驱动和自我更新，并产生了EP300的靶向弱点。

研究人员破译内源性TCF3-HLF的工作规则，并通过功能基因组学解剖其必需的转录成分和靶标。研究人员证明，TCF3-HLF在造血干细胞/髓系沿袭相关的（超级）增强子上招募HLF结合位点，以促进身份维持和自我更新。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，并募集组蛋白乙酰转移酶p300（EP300），从而更容易受到EP300抑制作用的影响。这项研究为这种致命白血病中的驱动转录依赖性靶向提供了框架。

据了解，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。

附：英文原文

Title: The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability

Author: Yun Huang, Brice Mouttet, Hans-Jrg Warnatz, Thomas Risch, Fabian Rietmann, Fabian Frommelt, Quy A. Ngo, Maria Pamela Dobay, Blerim Marovca, Silvia Jenni, Yi-Chien Tsai, Sren Matzk, Vyacheslav Amstislavskiy, Martin Schrappe, Martin Stanulla, Matthias Gstaiger, Beat Bornhauser, Marie-Laure Yaspo, Jean-Pierre Bourquin

Issue&Volume: November 14, 2019

Abstract: The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblasticleukemia subtype. Here we decipher the regulome of endogenous TCF3-HLF and dissectits essential transcriptional components and targets by functional genomics. We demonstratethat TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineageassociated (super-) enhancers to drive lineage identity and self-renewal. Among directtargets, hijacking an HLF binding site in a MYC enhancer cluster by TCF3-HLF activates a conserved MYC-driven transformation programcrucial for leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG and recruits histone acetyltransferasep300 (EP300), conferring susceptibility to EP300 inhibition. Our study provides aframework for targeting driving transcriptional dependencies in this fatal leukemia.

DOI: 10.1016/j.ccell.2019.10.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30478-7