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

研究目的：探究耐药性T细胞急性淋巴细胞白血病（T-cell Acute Lymphoblastic Leukemia, T-ALL）的三维基因组组织机制。实验方法：本研究采用多组表观基因组学、染色质构象及转录组学实验手段，探究GSI敏感型与GSI耐药性T-ALL细胞的染色质适应机制。研究结果：本研究发现，T/B细胞谱系决定性转录因子在GSI耐药性T-ALL细胞中呈差异表达，该现象驱动增强子转换与基因组折叠重编程事件，进而促进GSI耐药性的形成。研究结论：上述观测结果提示了一种通用机制：先驱因子（pioneering factors）的差异活性可被肿瘤细胞利用，以逃逸致癌信号的成瘾性依赖。整体实验设计：对亲本细胞与GSI耐药性DND41细胞，以及转导6天后分选得到的DND41-Res-Cas9对照细胞与LRmCherry2.1-EBF1-g7细胞开展原位Hi-C（in situ HiC）实验。