S1P-S1PR3-RAS promotes the progression of S1PR3hi TAL1+ T-cell acute lymphoblastic leukemia that can be effectively inhibited by an S1PR3 antagonist.

Abstract

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.

• Authors: 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
• Journal: Leukemia (Leukemia) Vol. 37 Issue 10 Pg. 1982-1993 (Oct 2023) ISSN: 1476-5551 [Electronic] England
• PMID: 37591940 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• 1-(4-chlorophenylhydrazono)-1-(4-chlorophenylamino)-3,3-dimethyl-2-butanone
• Core Binding Factor Alpha 2 Subunit
• T-Cell Acute Lymphocytic Leukemia Protein 1
• Basic Helix-Loop-Helix Transcription Factors
• TAL1 protein, human

Topics

• Humans
• Animals
• Mice
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Core Binding Factor Alpha 2 Subunit (genetics)
• T-Cell Acute Lymphocytic Leukemia Protein 1 (genetics, metabolism)
• Thymocytes (metabolism)
• Basic Helix-Loop-Helix Transcription Factors (genetics)