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

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 eve

SUBMITTER: Padder RA 

PROVIDER: S-EPMC12767518 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature