EBF1 nuclear repositioning instructs chromatin refolding to promote therapy resistance in T leukemic cells

• Published in: Molecular cell Vol. 82; no. 5; pp. 1003 - 1020.e15
• Main Authors: Zhou, Yeqiao, Petrovic, Jelena, Zhao, Jingru, Zhang, Wu, Bigdeli, Ashkan, Zhang, Zhen, Berger, Shelley L., Pear, Warren S., Faryabi, Robert B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-03-2022
• Subjects: Chromatin - genetics; chromatin folding; Drug Repositioning; drug resistance; EBF1; epigenetic adaptation; genome topology; Humans; lineage-determining transcription factors; pioneer transcription factors; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; T cell leukemia; T-Lymphocytes - metabolism; targeted therapy; TCF1; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; lineage-determining transcription factors; targeted therapy; chromatin folding; pioneer transcription factors; genome topology; epigenetic adaptation; EBF1; drug resistance; T cell leukemia; TCF1
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2022.01.015

Chromatin misfolding has been implicated in cancer pathogenesis; yet, its role in therapy resistance remains unclear. Here, we systematically integrated sequencing and imaging data to examine the spatial and linear chromatin structures in targeted therapy-sensitive and -resistant human T cell acute lymphoblastic leukemia (T-ALL). We found widespread alterations in successive layers of chromatin organization including spatial compartments, contact domain boundaries, and enhancer positioning upon the emergence of targeted therapy resistance. The reorganization of genome folding structures closely coincides with the restructuring of chromatin activity and redistribution of architectural proteins. Mechanistically, the derepression and repositioning of the B-lineage-determining transcription factor EBF1 from the heterochromatic nuclear envelope to the euchromatic interior instructs widespread genome refolding and promotes therapy resistance in leukemic T cells. Together, our findings suggest that lineage-determining transcription factors can instruct changes in genome topology as a driving force for epigenetic adaptations in targeted therapy resistance.
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•Genome refolding drives epigenetic adaptation and confers drug resistance in T-ALL•Drug-resistant T-ALL switches from TCF1-driven to EBF1-driven epigenetic program•Lineage-determining transcription factors EBF1 and TCF1 can instruct genome folding•EBF1 dynamically repositions within individual nuclei during resistance acquisition
Zhou et al. identify concerted and widespread restructuring of genome topology during targeted therapy resistance and reveal that the derepression and repositioning of the B-lineage-determining transcription factor EBF1 from the nuclear envelope to the interior drive genome folding reorganization and confer Notch-inhibitor resistance in leukemic T cells.