Abstract 2988: Loss of Rbm38 cooperates with mutant p53 to promote lymphomagenesis through downregulation of Pten

Abstract

Abstract The tumor suppressor TP53 is the most commonly mutated gene in human cancers and mutant p53 has a gain of function by promoting tumor progression, metastasis, and resistance to anticancer therapy. Interestingly, the RNA binding protein Rbm38, a critical regulator of mutant p53 translation, is frequently lost in tumors with mutant p53. To determine the role of the Rbm38-mutant p53 axis in tumorigenesis, we showed that loss of Rbm38 significantly alters the cancer susceptibility of mutant p53 knockin mice by shortening the lifespan, altering the tumor incidence, and promoting T-cell lymphomagenesis. To understand how Rbm38 deficiency promotes mutant p53 gain of function, we showed that loss of Rbm38 not only enhances mutant p53 expression but also decreases expression of tumor suppressor Pten, a critical regulator of T-cell development. Furthermore, we showed that Rbm38 is required for Pten expression by stabilizing Pten mRNA through an AU-rich element in its 3'UTR. Thus, we have uncovered a novel mechanism by which Pten is regulated by Rbm38 via mRNA stability. Our data also suggest that Rbm38 controls T-cell lymphomagenesis by concomitantly modulating mutant p53 and Pten, which may be explored as a therapeutic strategy for the treatment of T-cell malignancies. Citation Format: Jin Zhang, Heejung yang, Yanhong Zhang, Mingyi Chen, Xinbin Chen. Loss of Rbm38 cooperates with mutant p53 to promote lymphomagenesis through downregulation of Pten [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2988.