PO.MCB07.04 · 分子与细胞生物学
协同靶向mSWI/SNF和UTX揭示T细胞急性淋巴细胞白血病的一种新型联合治疗
Synergistic targeting of mSWI/SNF and UTX reveals a novel combination therapy in T-cell acute lymphoblastic leukemia
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摘要 Abstract
中文摘要
致癌转录因子（TFs）表达失调是T细胞急性淋巴细胞白血病（T-ALL）的一个关键特征。这些异常破坏了下游靶基因严格调控的时空表达，并重新连线转录程序，最终形成一种"转录成瘾"状态。我们发现，T-ALL中RUNX1和NOTCH1等致癌因子招募mSWI/SNF染色质重塑复合体，以调节靶基因位点的染色质可及性，从而启动和维持致癌转录网络。使用SMARCA2/4 ATP酶抑制剂（FHD-286）或靶向SMARCA蛋白的PROTAC降解剂（ACBI-1）抑制mSWI/SNF功能，可诱导凋亡并损害T-ALL细胞生长。为进一步剖析T-ALL细胞对mSWI/SNF复合体的功能依赖性，我们在经FHD-286或ACBI-1处理的T-ALL细胞中进行了全基因组CRISPR敲除（KO）筛选。这些筛选显示，Mediator复合体的多个成员是高置信度靶点，单独敲除其中任一成员即足以将T-ALL细胞从抑制剂诱导的细胞死亡中挽救出来。相反，敲除组蛋白去甲基化酶UTX使T-ALL细胞对mSWI/SNF抑制敏感化。值得注意的是，与野生型（WT）对照相比，UTX KO细胞中FHD-286处理的IC50显著降低。此外，与经FHD-286处理的WT异种移植相比，UTX KO T-ALL异种移植小鼠在接受FHD-286治疗后生存改善。当T-ALL细胞或患者来源异种移植（PDXs）与组蛋白去甲基化酶抑制剂GSK-J4和FHD-286共同处理时，出现协同效应。转录组学分析表明，在经FHD-286处理的UTX KO T-ALL细胞中，促进核糖体和线粒体功能的基因大幅下调，而在同样处理的WT细胞中则未出现，提示UTX在基因调控中具有此前未被认识的作用。总体而言，这些发现表明，同时靶向mSWI/SNF复合体和UTX可能代表一种创新的T-ALL联合治疗策略。
查看英文原文 English abstract
Dysregulated expression of oncogenic transcription factors (TFs) is a critical hallmark of T-cell acute lymphoblastic leukemia (T-ALL). These aberrations disrupt the tightly regulated spatial-temporal expression of downstream target genes and rewire transcriptional programs, culminating in a state of “transcription addiction”. We show that oncogenic factors such as RUNX1 and NOTCH1 in T-ALL recruit the mSWI/SNF chromatin-remodeling complex to modulate chromatin accessibility at target gene loci to initiate and maintain oncogenic transcriptional networks. Inhibiting mSWI/SNF function with SMARCA2/4 ATPase inhibitors (FHD-286) or PROTAC degraders (ACBI-1) targeting the SMARCA protein induces apoptosis and impairs T-ALL cell growth. To further dissect the functional dependencies of T-ALL cells on the mSWI/SNF complex, we performed genome-wide CRISPR knockout (KO) screens in T-ALL cells treated with FHD-286 or ACBI-1. These screens revealed that multiple members of the Mediator complex were high-confidence targets whose individual knockout was sufficient to rescue T-ALL cells from inhibitor-induced cell death. In contrast, knockout of the histone demethylase UTX sensitized T-ALL cells to mSWI/SNF inhibition. Notably, the IC50 of FHD-286 treatment decreased significantly in UTX KO cells compared to wild-type (WT) controls. Furthermore, UTX KO T-ALL xenograft mice showed improved survival when treated with FHD-286 compared to FHD-286-treated WT xenografts. A synergistic effect emerged when T-ALL cells or patient-derived xenografts (PDXs) were co-treated with GSK-J4, a histone demethylase inhibitor, and FHD-286. Transcriptomic analyses indicated that genes promoting ribosomal and mitochondrial function were substantially downregulated in UTX KO T-ALL cells treated with FHD-286 but not in similarly treated WT cells, suggesting a previously unrecognized role of UTX in gene regulation. Overall, these findings demonstrate that simultaneously targeting the mSWI/SNF complex and UTX may represent an innovative combinatorial strategy for T-ALL treatment.
利益披露 Disclosure
S. Tan, None..
H. Kim, None..
Z. Lee, None..
L. Chua, None..
S. Takaomi, None..
A. Yeoh, None.