2. Academic Validation
  3. PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia

PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia

  • bioRxiv. 2025 Dec 24:2025.12.22.696045. doi: 10.64898/2025.12.22.696045.
Rayees A Padder 1,  Thu Le Le 2,  Emily Hyde 3,  Maria E D Rubio 2,  Eric Chiles 2,  Namratha Sheshadri 4,  Kelly Mulraney 5,  Wei-Xing Zong 4,  Xiaoyang Su 2 6,  Daniel Herranz 2 7 8,  Alexander J Valvezan 1 2 7
Affiliations

Affiliations

  • 1 Center for Advanced Biotechnology and Medicine, Piscataway, NJ 08854.
  • 2 Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08901.
  • 3 Molecular Biosciences Program, Rutgers University, Piscataway, NJ 08854.
  • 4 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854.
  • 5 Rutgers University Animal Care Unit, In Vitro Research Service Core, Piscataway, NJ 08854.
  • 6 Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901.
  • 7 Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854.
  • 8 Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901.
PMID: 41497604 DOI: 10.64898/2025.12.22.696045
Abstract

Loss of the tumor suppressor PTEN is common in T-cell acute lymphoblastic leukemia (T-ALL), and is associated with poor prognosis. PTEN-loss drives robust activation of Akt/mTORC1 signaling to promote leukemic cell growth. We find that PTEN-loss in T-ALL confers dependence on the guanylate nucleotide synthesis enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) for cell growth and viability. This metabolic vulnerability is dependent on sustained mTORC1 signaling and can be exploited using clinically approved IMPDH inhibitors to selectively kill PTEN-deficient T-ALL cells, and extend survival in genetic and xenograft T-ALL models in mice. Mechanistically, IMPDH inhibitors cause early DNA replication stress, followed by DNA damage. In contrast to treatment with mTORC1 inhibitors, these events culminate in robust and selective cell death in PTEN-deficient T-ALL cells. These findings reveal a targetable metabolic vulnerability in T-ALL, which could provide rationale for repurposing clinically approved IMPDH inhibitors.

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