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<p>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy arising from abnormal T-cell differentiation. Conventional treatment strategies remain suboptimal, and no effective targeted therapy is currently available. Here, we found that ASS1 is significantly upregulated in T-ALL and is associated with poor prognosis. Inhibition of ASS1 expression markedly suppresses T-ALL progression both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, RNA-seq revealed that ASS1 depletion led to a significant downregulation of one-carbon metabolism and ribose synthesis pathways, and the mTORC1/c-Myc signaling pathway. Experimental validation confirmed that mTORC1/c-Myc signaling was significantly downregulated upon ASS1 blockage. Furthermore, the intracellular arginine level was significantly reduced following ASS1 knockdown, while supplementation with arginine enhanced mTORC1/c-Myc pathway activity. Notably, restoration of c-Myc effectively rescued T-ALL cells from the suppressive effects induced by ASS1 depletion. Collectively, our findings demonstrate that ASS1 supports mTORC1/c-Myc pathway activity by regulating arginine availability, thereby promoting the survival of T-ALL cells and leukemia progression.</p>

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ASS1 facilitates T-ALL progression via the arginine-mediated mTORC1/c-Myc signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月15日

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  • Zijian Zhang,
  • Xiyu Liu,
  • Qifang Wu,
  • Jianwei Liang,
  • Yuan Zhao,
  • Jiaqi Deng,
  • Yuqing Wang,
  • Qingrun Yu,
  • Zishan Ye,
  • Haichuan Zhu,
  • Jian Lin

摘要

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy arising from abnormal T-cell differentiation. Conventional treatment strategies remain suboptimal, and no effective targeted therapy is currently available. Here, we found that ASS1 is significantly upregulated in T-ALL and is associated with poor prognosis. Inhibition of ASS1 expression markedly suppresses T-ALL progression both in vitro and in vivo. Mechanistically, RNA-seq revealed that ASS1 depletion led to a significant downregulation of one-carbon metabolism and ribose synthesis pathways, and the mTORC1/c-Myc signaling pathway. Experimental validation confirmed that mTORC1/c-Myc signaling was significantly downregulated upon ASS1 blockage. Furthermore, the intracellular arginine level was significantly reduced following ASS1 knockdown, while supplementation with arginine enhanced mTORC1/c-Myc pathway activity. Notably, restoration of c-Myc effectively rescued T-ALL cells from the suppressive effects induced by ASS1 depletion. Collectively, our findings demonstrate that ASS1 supports mTORC1/c-Myc pathway activity by regulating arginine availability, thereby promoting the survival of T-ALL cells and leukemia progression.