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In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation
Genes & Development ( IF 7.5 ) Pub Date : 2022-04-01 , DOI: 10.1101/gad.349115.121
Glòria Mas 1 , Fabio Santoro 2, 3 , Enrique Blanco 1 , Gianni Paolo Gamarra Figueroa 1 , François Le Dily 1 , Gianmaria Frigè 2, 3 , Enrique Vidal 1 , Francesca Mugianesi 1, 4 , Cecilia Ballaré 1 , Arantxa Gutierrez 1 , Aleksandra Sparavier 1, 4 , Marc A Marti-Renom 1, 4, 5, 6 , Saverio Minucci 2, 3 , Luciano Di Croce 1, 5, 6
Affiliation  

Genome organization plays a pivotal role in transcription, but how transcription factors (TFs) rewire the structure of the genome to initiate and maintain the programs that lead to oncogenic transformation remains poorly understood. Acute promyelocytic leukemia (APL) is a fatal subtype of leukemia driven by a chromosomal translocation between the promyelocytic leukemia (PML) and retinoic acid receptor α (RARα) genes. We used primary hematopoietic stem and progenitor cells (HSPCs) and leukemic blasts that express the fusion protein PML-RARα as a paradigm to temporally dissect the dynamic changes in the epigenome, transcriptome, and genome architecture induced during oncogenic transformation. We found that PML-RARα initiates a continuum of topologic alterations, including switches from A to B compartments, transcriptional repression, loss of active histone marks, and gain of repressive histone marks. Our multiomics-integrated analysis identifies Klf4 as an early down-regulated gene in PML-RARα-driven leukemogenesis. Furthermore, we characterized the dynamic alterations in the Klf4 cis-regulatory network during APL progression and demonstrated that ectopic Klf4 overexpression can suppress self-renewal and reverse the differentiation block induced by PML-RARα. Our study provides a comprehensive in vivo temporal dissection of the epigenomic and topological reprogramming induced by an oncogenic TF and illustrates how topological architecture can be used to identify new drivers of malignant transformation.

中文翻译:

急性早幼粒细胞白血病进展的体内时间分辨率揭示了 Klf4 在抑制早期白血病转化中的作用

基因组组织在转录中起着关键作用,但转录因子 (TF) 如何重新连接基因组的结构以启动和维持导致致癌转化的程序仍然知之甚少。急性早幼粒细胞白血病 (APL) 是一种致命的白血病亚型,由早幼粒细胞白血病 (PML) 和视黄酸受体α (RARα) 基因之间的染色体易位驱动。我们使用表达融合蛋白 PML-RARα 的原代造血干细胞和祖细胞 (HSPC) 和白血病原始细胞作为范式,暂时剖析致癌转化过程中诱导的表观基因组、转录组和基因组结构的动态变化。我们发现 PML-RARα 引发了一系列拓扑变化,包括从 A 到 B 区室的转换、转录抑制、失去活性组蛋白标记,获得抑制组蛋白标记。我们的多组学综合分析确定Klf4作为 PML-RARα 驱动的白血病发生中的早期下调基因。此外,我们描述了 APL 进展过程中Klf4 顺式调节网络的动态变化,并证明异位Klf4过表达可以抑制自我更新并逆转 PML-RARα 诱导的分化阻滞。我们的研究对致癌 TF 诱导的表观基因组和拓扑重编程进行了全面的体内时间剖析,并说明了拓扑结构如何用于识别恶性转化的新驱动因素。
更新日期:2022-04-01
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