TARDBP drives T‐cell acute lymphoblastic leukemia progression by binding MDM2 mRNA, involving β‐catenin pathway

Abstract T‐cell acute lymphoblastic leukemia (T‐ALL) is a dangerous hematological malignancy. The trans‐activation response DNA binding protein (TARDBP), an RNA/DNA binding protein, is involved in the growth and metastasis of multiple cancers. However, TARDBP has not been reported in T‐ALL. It was found that TARDBP was highly expressed in pediatric T‐ALL samples by microarray GSE26713 (log2 fold change >1, p < .05). Herein, TARDBP was silenced and overexpressed by lentivirus transduction in T‐ALL cell lines, including Jurkat and Molt4 cells. In vitro, silencing TARDBP inhibited T‐ALL cell proliferation and cycle progression and accelerated cell apoptosis, while overexpressing TARDBP induced the opposite effects. In addition, we investigated whether the β‐catenin pathway could be activated by TARDBP in T‐ALL cells. Moreover, XAV‐939, a β‐catenin inhibitor, was capable of suppressing the malignant phenotypes in TARDBP‐overexpressed T‐ALL cells. In vivo, TARDBP‐silenced or TARDBP‐overexpressed T‐ALL cells were injected into mice. We found that TARDBP promoted T‐ALL cell growth in the spleens and bone marrows of mice. On the basis of GSE26713, there was a significant correlation between TARDBP and mouse double minute 2 (MDM2). The RIP‐PCR assay demonstrated that TARDBP bound MDM2 mRNA in T‐ALL cells. The rescue experiments further revealed the roles of the TARDBP/MDM2 axis in T‐ALL cell phenotypes, which was also reflected by mRNA‐seq. In aggregate, we explored a promising biomarker, TARDBP, for T‐ALL treatment. The underlying mechanisms might involve the interaction with MDM2 mRNA and the regulation of the β‐catenin pathway.