A novel ATG4B-SESN3 axis promotes the growth of T-cell acute lymphoblastic leukemia cells

ATG4B, a cysteine protease, plays crucial roles in the autophagy process and is implicated in various human diseases including cancers. However, little is known about ATG4B in T- cell acute lymphoblastic leukemia (T-ALL), a fatal hematological malignancy. Although ATB4B ablation hampers cancer cell growth, the molecular insight is not elucidated yet. Herein, we showed that ATG4B had significantly higher expression in T-ALL cells than control cells. ATG4B ablation through RNA interference or CRISPR/Cas9-mediated gene knockout inhibited T-ALL cell growth in vitro and in vivo. In contrast, Atg4b depletion had mild effects on normal hematopoiesis and T-cell development. Mechanistically, RNA-seq analysis revealed that ATG4B silencing significantly enhanced the expression of sestrin 3 (SESN3). Subsequent studies indicated that SESN3 plays a tumor suppressor role in T-ALLcells via a strong inhibition of protein translation caused by S6K inactivation. Rescue experiment showed SESN3 silencing partially restored the growth inhibitory effect of ATG4B ablation. Importantly, ATG4B inhibitor exhibited anti-leukemia activity in a patient-derived xenograft (PDX) model. Taken together, this study demonstrates that a novel ATG4B-SESN3 pathway plays a crucial role in T-cell leukemogenesis and targeting ATG4B provides an optional strategy for T-ALL treatment. Overall design: To investigate the molecular mechanisms by which ATG4B silencing hampers T-ALL cell growth, RNA-Seq data were generated with ATG4B-silenced and control (scrambled) Jurkat cells from 3 independent RNA extracts. The differentially expressed transcripts comparing ATG4B-silenced cells with scrambled cells are displayed.