PTBP2 promotes cell survival and autophagy in Chronic Myeloid Leukemia by stabilizing BNIP3

Polypyrimidine tract binding protein 2 (PTBP2) regulates alternative splicing in neuronal, muscle, and Sertoli cells. PTBP2 and its paralog, PTBP1, which plays a role in B-cell development, was found to be expressed aberrantly in myeloid leukemia. Genetic ablation of Ptbp2 in the cells resulted in decreased cellular proliferation and repopulating ability, decreased reactive oxygen species (ROS), and altered mitochondrial morphology. The sensitivity of CML cells to imatinib increased after the knockout of Ptbp2. RNA immunoprecipitation followed by sequencing (RIP-seq) and functional assays confirmed that PTBP2 binds to Bcl-2 Interacting Protein 3 (Bnip3)-3-UTR and stabilizes its expression. Our study also suggests that PTBP2 promotes autophagy, as evidenced by the low levels of LC3-II expression in Ptbp2-knockout cells treated with bafilomycin A1. This was restored upon overexpression of Bnip3 in the knockout cells. Finally, we observed that KCL22 cells gave rise to malignant tumors compared to KCL22-Ptbp2 KO cells when injected subcutaneously in the flanks of mice. Thus, PTBP2 promotes cell proliferation and tumor formation while also enhancing autophagy through Bnip3, contributing to CML's progression.