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ACUTE LYMPHOBLASTIC LEUKEMIA

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

Leukemia volume 37, pages 1982–1993 (2023)Cite this article

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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.

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Fig. 1: The highly expressed S1PR3 is associated with inferior prognosis of T-ALL.
Fig. 2: S1P-S1PR3 sustains the progression of TAL1+ T-ALL cells.
Fig. 3: The oncogenic TAL1-RUNX1 complex up-regulates the expression of S1PR3 in T-ALL cells.
Fig. 4: S1P-S1PR3-RAS sustains the survival of TAL1+ T-ALL cells.
Fig. 5: S1P-S1PR3 sustains the RAS signal in T-ALL cells.
Fig. 6: TY-52156 displays anti-leukemic effects in a patient-derived xenograft mouse model of S1PR3hi TAL1+ T-ALL cells.

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Data availability

All data needed to evaluate the conclusions in the paper are presented in the paper and/or the Supplementary Materials. The raw RNA-seq data reported in this paper, including T-ALL samples, HSPCs (lin−CD34+), and thymocytes derived from non-hematological malignant donors, were deposited in the Genome Sequence Archive database under accession number HRA002558.

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Acknowledgements

We thank the National Clinical Research Center for Child Health and Disorders for the use of their Shared Services (Flow Cytometry Laboratory, Animal Facility, and Experimental Pathology Laboratory) for completing this research. This study was supported by the National Natural Science Foundation of China (#81870126, #82070167, and #82270160 to LZ; #81900190 to YS) and The Chongqing Science and Technology Bureau Major Project (cstc2020jcyj-msxmX0782 to YS). We are grateful to Professors Bing Liu, Yufeng Shi, and Qing Lu for helping us to revise our paper and Figures. Finally, we are greatly indebted to the T-ALL patients and their families for their support and willingness to participate in the study.

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  1. These authors contributed equally: Dan Zhu, Tingting Jiang, Deyu Ma.

Authors and Affiliations

  1. Center for Clinical Molecular Medicine, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, The Children’s Hospital of Chongqing Medical University, Chongqing, China

    Dan Zhu, Tingting Jiang, Deyu Ma, 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, Jie Yu, Yi Shu & Lin Zou

  2. Clinical Research Unit of Children’s Hospital, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Hongyang Zhang, Zijun Yan, Ziyang Cao & Lin Zou

  3. Division of Hematology, The Children’s Hospital of Chongqing Medical University, Chongqing, China

    Haiyan Liu & Jie Yu

  4. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

    Hui Zhao

  5. Kunming Institute of Zoology, Chinese Academy of Sciences, The Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Hong Kong SAR, China

    Hui Zhao

  6. Hong Kong Branch of CAS Center for Excellence in Animal Evolution and Genetics, The Chinese University of Hong Kong, Hong Kong SAR, China

    Hui Zhao

  7. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA

    Tong-Chuan He

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  1. Dan Zhu
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Contributions

Conceptualization: LZ, YS, and JY. Methodology: DZ, TTJ, DYM, WQL, JZ, and YS. Investigation: MYG, HBW, ZYL, HYS, LMZ, and LZ. Data curation: HYZ, TTJ, and JY. Formal analysis: HYL, GF, DYP, BJY, and ZJY. Visualization: FIT, ZDL, LS, ZYC, and ST. Writing: YS, LZ, JY, TCH, ZJY, and HZ. All the authors have read and approved the paper.

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Correspondence to Jie Yu, Yi Shu or Lin Zou.

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Zhu, D., Jiang, T., Ma, D. et al. S1P-S1PR3-RAS promotes the progression of S1PR3hi TAL1+ T-cell acute lymphoblastic leukemia that can be effectively inhibited by an S1PR3 antagonist. Leukemia 37, 1982–1993 (2023). https://doi.org/10.1038/s41375-023-02000-0

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