超级增强子调控基因FYB1通过激活IGLL1促进T细胞急性淋巴细胞白血病进展,Journal of Immunology Research

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超级增强子调控基因FYB1通过激活IGLL1促进T细胞急性淋巴细胞白血病进展
Journal of Immunology Research ( IF 3.5 ) Pub Date : 2023-9-19 , DOI: 10.1155/2023/3804605
Kunlong Zhang _{1,

2} , Jun Lu ₃ , Fang Fang ₄ , Yongping Zhang ₁ , Juanjuan Yu ₁ , Yanfang Tao ₄ , Wenyuan Liu ₂ , Lihui Lu ₁ , Zimu Zhang ₄ , Xinran Chu ₃ , Jianwei Wang ₄ , Xiaolu Li ₄ , Yuanyuan Tian _{3,

4} , Zhiheng Li ₁ , Qian Li ₁ , Xu Sang ₁ , Li Ma ₁ , Ningling Wang ₂ , Jian Pan ₄ , Shaoyan Hu ₃

Affiliation

背景。T细胞急性淋巴细胞白血病（T-ALL）源自T祖细胞，是一种侵袭性血液系统恶性肿瘤，占儿童ALL的15%和成人ALL的25%。超级增强子 (SE) 由基因组附近的推定增强子组成，对于细胞身份和多种癌症的发病机制至关重要。FYB1 属于细胞质连接蛋白组，对于 TCR 信号传导至关重要，并在肿瘤发病机制和转移方面得到广泛研究。剖析 FYN 结合蛋白 1 (FYB1) 在 T-ALL 中的作用有望改善 T-ALL 的治疗结果和预后。方法。在本研究中，使用源自 T-ALL 细胞系、AML 细胞系和造血干细胞和祖细胞 (HSPC) 的公共 H3K27ac ChIP-seq 数据对 SE 进行了探索。通过RNA-seq鉴定FYB1基因的下游靶标。在体外和/或体内评估了 shRNA 介导的 FYB1 和免疫球蛋白 lambda 样多肽 1 (IGLL1) 下调对 T-ALL 细胞自我更新的影响。结果。根据癌细胞系百科全书数据库，作为 SE 驱动的基因，FYB1 在 T-ALL 中过度表达。在体外，敲低 FYB1 会导致 T-ALL 细胞生长并增强细胞凋亡。在体内，FYB1的下调通过抑制肿瘤生长并提高生存率来显着减轻疾病负担。敲除 FYB1 会导致 IGLL1 的表达显着降低，IGLL1 也是 T-ALL 中 SE 驱动的基因。作为FYB1的下游靶标，IGLL1在抑制T-ALL细胞生长方面发挥与FYB1相似的作用。结论。我们的结果表明，FYB1 基因通过激活 IGLL1 在调节 T-ALL 细胞的自我更新中发挥重要作用，是 T-ALL 患者的一个有前途的治疗靶点。

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Super Enhancer Regulatory Gene FYB1 Promotes the Progression of T Cell Acute Lymphoblastic Leukemia by Activating IGLL1

Background. Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL. Methods. In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo. Results. As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells. Conclusion. Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients.

更新日期：2023-09-19

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