EBF1 nuclear repositioning instructs chromatin refolding to promote therapy resistance in T leukemic cells.[DND41_HiC]

Purpose: To investigate the mechanisms of 3D genome organization in drug-resistant T-ALL Methods: We used multiple epigenomics, chromatin conformation, and transcriptomic assays to study the mechanisms of chromatin adaptation in GSI-sensitive and GSI-resistant T-ALL Results: We report here that T/B cell lineage determining transcription factors are differentially expressed in GSI-resistant T-ALL cells, driving enhancer switching and genome folding reorganization events to promote GSI-resistance. Conclusions: These observations suggest a general mechanism that diffenrential activity of pioneering factors can be exploited to evade addiction to oncogenic signals. Overall design: In situ HiC was performed in parental and GSI-resistant DND41 cells, and DND41-Res-Cas9 control and LRmCherry2.1-EBF1-g7 cells sorted 6 days post transduction.