PIP4K2A depletion suppresses AKT signaling and enhances chemotherapy sensitivity in T-cell lymphoblastic lymphoma cells.

T-cell lymphoblastic lymphoma (T-LBL) is an aggressive malignancy of immature T cells characterized by rapid proliferation and frequent activation of pro-survival pathways such as PI3K/AKT/mTORC1 signaling. Although multi-agent chemotherapy can induce remission, relapsed disease is often refractory, underscoring the need to identify vulnerabilities that enhance therapeutic response. Previous studies showed that genetic ablation of Pip4k2a and Pip4k2b protects Trp53-null mice from thymic lymphoma, implicating these lipid kinases in T-cell lymphomagenesis. Here, we show that knockdown of PIP4K2A and PIP4K2B reduced AKT signaling, inhibited proliferation, and increased sensitivity to multiple chemotherapeutic agents in Sup-T1 cells, a human T-LBL cell line. PIP4K2A knockdown largely recapitulated the enhanced chemosensitivity observed following combined PIP4K2A/2B depletion, whereas PIP4K2B knockdown had a more limited effect. Unexpectedly, two structurally distinct PIP4K2A inhibitors failed to suppress Sup-T1 proliferation or viability, suggesting that the kinase supports AKT signaling through an activity-independent mechanism. Although individual knockdown of PIP4K2A or PIP4K2B produced only modest effects on S6K phosphorylation, combined depletion markedly reduced mTORC1 activity. Together, these findings identify PIP4K2A as a positive regulator of AKT signaling in T-LBL cells and provide a motivation for further investigating its non-catalytic functions in chemotherapy response.