S1P-S1PR3-RAS有助于S1PR3高表达的TAL1+ T-细胞急性淋巴细胞性白血病的进展，而这种进展可以被S1PR3拮抗剂有效地抑制。
S1P-S1PR3-RAS promotes the progression of S1PR3hi TAL1+ T-cell acute lymphoblastic leukemia that can be effectively inhibited by an S1PR3 antagonist.
发表日期：2023 Aug 17
作者：
Dan Zhu, Tingting Jiang, Deyu Ma, Hongyang Zhang, Jia Zhang, Wenqiong Lv, Maoyuan Gong, Haobiao Wang, Ziyang Liu, Hongyu Su, Lamei Zeng, Shan Liu, Shi Tang, Bijie Yang, Filippus I Tshavuka, Guo Fu, Zidai Liu, Danyi Peng, Haiyan Liu, Zijun Yan, Ziyang Cao, Hui Zhao, Tong-Chuan He, Jie Yu, Yi Shu, Lin Zou
来源：
Stem Cell Research & Therapy
摘要：
TAL1+ T细胞急性淋巴细胞白血病(T-ALL)是一种具有不良预后的独特亚型白血病。通过合作与活化因子，包括RUNX1、GATA3和MYB，TAL1癌蛋白增强了未成熟胸腺细胞的自主性，并在T-ALL的发展中起重要作用。然而，这个过程尚不完全理解。通过研究多个队列的T-ALL的转录组和预后，我们发现S1PR3在一组TAL1+ T-ALL(S1PR3高表达的TAL1+ T-ALL)中高度表达，并显示出不良预后。通过药理和遗传方法，我们确定了S1P-S1PR3在TAL1+ T-ALL细胞中特定的维持生存作用。在T-ALL细胞中，TAL1-RUNX1通过结合S1PR3基因的增强子区域上调了S1PR3的表达。通过超活化的S1P-S1PR3，T-ALL细胞以部分激活KRAS信号的方式快速增长。最后，我们评估了S1PR3抑制剂TY-52156在T-ALL移植瘤小鼠模型中的效果。我们发现TY-52156可以有效减缓白血病进展，并延长S1PR3高表达的TAL1+ T-ALL移植瘤的生存时间。我们的发现表明S1PR3在S1PR3高表达的TAL1+ T-ALL中发挥了重要的致癌作用，并可能成为一个有前景的治疗靶点。© 2023. 作者,独家授权Springer Nature Limited.
TAL1+ T-cell acute lymphoblastic leukemia (T-ALL) is a distinct subtype of leukemia with poor outcomes. Through the cooperation of co-activators, including RUNX1, GATA3, and MYB, the TAL1 oncoprotein extends the immature thymocytes with autonomy and plays an important role in the development of T-ALL. However, this process is not yet well understood. Here, by investigating the transcriptome and prognosis of T-ALL from multiple cohorts, we found that S1PR3 was highly expressed in a subset of TAL1+ T-ALL (S1PR3hi TAL1+ T-ALL), which showed poor outcomes. Through pharmacological and genetic methods, we identified a specific survival-supporting role of S1P-S1PR3 in TAL1+ T-ALL cells. In T-ALL cells, TAL1-RUNX1 up-regulated the expression of S1PR3 by binding to the enhancer region of S1PR3 gene. With hyperactivated S1P-S1PR3, T-ALL cells grew rapidly, partly by activating the KRAS signal. Finally, we assessed S1PR3 inhibitor TY-52156 in T-ALL patient-derived xenografts (PDXs) mouse model. We found that TY-52156 attenuated leukemia progression efficiently and extended the lifespan of S1PR3hi TAL1+ T-ALL xenografts. Our findings demonstrate that S1PR3 plays an important oncogenic role in S1PR3hi TAL1+ T-ALL and may serve as a promising therapeutic target.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.