VIB Center for Cancer Biology, Leuven, Belgium.
KU Leuven Center for Human Genetics, Leuven, Belgium.
Blood. 2019 Oct 17;134(16):1323-1336. doi: 10.1182/blood.2019000015.
The polycomb repressive complex 2, with core components EZH2, SUZ12, and EED, is responsible for writing histone 3 lysine 27 trimethylation histone marks associated with gene repression. Analysis of sequence data from 419 T-cell acute lymphoblastic leukemia (T-ALL) cases demonstrated a significant association between SUZ12 and JAK3 mutations. Here we show that CRISPR/Cas9-mediated inactivation of Suz12 cooperates with mutant JAK3 to drive T-cell transformation and T-ALL development. Gene expression profiling integrated with ChIP-seq and ATAC-seq data established that inactivation of Suz12 led to increased PI3K/mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), and WNT signaling. Moreover, a drug screen revealed that JAK3/Suz12 mutant leukemia cells were more sensitive to histone deacetylase (HDAC)6 inhibition than JAK3 mutant leukemia cells. Among the broad genome and gene expression changes observed on Suz12 inactivation, our integrated analysis identified the PI3K/mTOR, VEGF/VEGF receptor, and HDAC6/HSP90 pathways as specific vulnerabilities in T-ALL cells with combined JAK3 and SUZ12 mutations.
多梳抑制复合物 2 由核心成分 EZH2、SUZ12 和 EED 组成，负责书写与基因抑制相关的组蛋白 3 赖氨酸 27 三甲基化组蛋白标记。对 419 例 T 细胞急性淋巴细胞白血病 (T-ALL) 病例的序列数据分析表明，SUZ12 与 JAK3 突变之间存在显著关联。在这里，我们表明 CRISPR/Cas9 介导的 Suz12 失活与突变型 JAK3 合作，驱动 T 细胞转化和 T-ALL 发展。基因表达谱分析与 ChIP-seq 和 ATAC-seq 数据相结合，确定 Suz12 的失活导致 PI3K/哺乳动物雷帕霉素靶蛋白 (mTOR)、血管内皮生长因子 (VEGF) 和 WNT 信号的增加。此外，药物筛选表明，JAK3/Suz12 突变白血病细胞比 JAK3 突变白血病细胞对组蛋白去乙酰化酶 (HDAC)6 抑制更敏感。在 Suz12 失活观察到的广泛基因组和基因表达变化中，我们的综合分析确定了 PI3K/mTOR、VEGF/VEGF 受体和 HDAC6/HSP90 途径在具有 JAK3 和 SUZ12 突变的 T-ALL 细胞中是特定的脆弱性。
