• ORP4L deletion blocks Tax-induced T-cell leukemia while engineering ORP4L expression in T-cells results in T-cell leukemia in mice

  • Loss of miR-31 induced by Tax releases ORP4L expression that initiates T-cell deterioration, but ORP4L inhibition eliminates ATL in PDX mice

Human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL), but the mechanism underlying its initiation remains elusive. Here we report that ORP4L is expressed in ATL cells but not normal T-cells. ORP4L ablation completely blocks T-cell leukemogenesis induced by the HTLV-1 oncoprotein Tax in mice while engineering ORP4L expression in T-cells results in T-cell leukemia in mice, suggesting the oncogenic properties and prerequisite of ORP4L for the initiation of T-cell leukemogenesis. For molecular insight, loss of miR-31 caused by HTLV-1 induces ORP4L expression in T-cells. ORP4L interacts with PI3Kδ to promote PI(3,4,5)P3 generation, contributing to AKT hyperactivation, NF-κB-dependent p53 inactivation induced pro-oncogenes expression and T-cell leukemogenesis. Consistently, ORP4L ablation eliminates human ATL cells in patient-derived xenograft ATL models. These results reveal a plausible mechanism of T-cells deterioration by HTLV-1 that can be therapeutically targeted.

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