CLN7 suppression induces apoptosis via mTOR-regulated and chaperone-mediated autophagy in myeloid leukemia cells.

Refractory disease and relapse continue to impede effective treatment of myeloid leukemia, despite substantial progress in therapeutic approaches. Emerging evidence implicates lysosomal ion channels in the regulation of cell death pathways, highlighting these channels as viable targets for therapeutic intervention. This study identified elevated expression of the lysosomal ion channel CLN7 in myeloid leukemia cells. Suppression of CLN7 triggered apoptosis, inhibited cellular proliferation, and markedly reduced the abundance of oncogenic proteins. Mechanistically, CLN7 inhibition promoted nuclear translocation of TFEB by downregulating mTOR signaling, thereby enhancing lysosomal biogenesis and macroautophagy. Notably, CLN7 suppression selectively accelerated chaperone-mediated autophagic degradation of BCR-ABL through cathepsin B (CTSB) upregulation. In addition, inhibition of CLN7 induced autophagy-mediated apoptosis, which led to significant impairment of leukemogenic potential. Co-treatment with chemotherapeutic agents and CLN7 suppression enhanced therapeutic efficacy in myeloid leukemia cells. Finally, suppression of CLN7 markedly reduced tumor growth in human xenograft models without compromising normal hematopoietic function. These findings establish CLN7 as a critical regulator of leukemic cell survival, representing a promising therapeutic target for myeloid leukemia.