An Anti-Apoptotic Protein C17ORF58 Is Critical for the Maintenance of Human Peripheral T-Cell Lymphomas By Suppressing BBC3-Induced Apoptosis

Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of T- and NK-cell malignancies characterized by diverse cells of origin, varied cytogenetic, molecular, and morphological phenotypes, and antigen variability. They account for approximately 15% of non-Hodgkin lymphomas. Despite treatments with conventional chemotherapy like CHOP and R-CHOP, as well as targeted therapies such as belinostat, romidepsin, pralatrexate, and brentuximab vedotin, the overall 5-year survival rate remains low at 20-30%. Thus, improving PTCL therapies necessitates the identification of novel targets crucial for lymphoma cell survival.

C17ORF58 is an uncharacterized human gene that encodes several isoforms with molecular weights of 37 kDa, 11 kDa, and 9 kDa. The longest isoform encodes a protein with a predicted consensus disordered region and signal peptide in the N-terminal region, as well as a Netrin-like domain in the C-terminal region. Such structural features are found in complement proteins and various proteases, but its function remains unclear. C17ORF58 is overexpressed in the vast majority of human PTCL subtypes, including Anaplastic Large Cell Lymphoma, Angioimmunoblastic Lymphoma, and PTCL-Not Otherwise Specified (PTCL-NOS). The mouse homolog of C17ORF58, 1810010H24Rik, is highly expressed in various normal tissues, including the lungs, heart, kidneys, and skeletal muscle, but at low levels in the brain. In hematopoietic organs, 1810010H24Rik protein expression varies, with low levels in the bone marrow and medium levels in the thymus and spleen, potentially indicating a role in blood cell maturation. Interestingly, the protein is up-regulated in mouse T-cell lymphoma induced by the loss of DNA methyltransferase 3a, suggesting that, as in humans, increased expression is closely linked to PTCL development.

The downregulation of C17ORF58 does not affect the proliferation of normal primary human T-cells or the human embryonic kidney cell line HEK293T. In contrast, the loss of C17ORF58 function in T-cell lymphoma and leukemia lines T8ML-1 and Jurkat inhibits proliferation by inducing G2-M arrest and apoptosis. Loss of C17ORF58 leads to the upregulation of numerous signaling pathways, including p53 and MAPK signaling, apoptosis, angiogenesis, and hypoxia. Consistently, C17ORF58 knockdown in T-cell lines results in the upregulation of numerous pro-apoptotic genes, including BBC3 (PUMA), EPAS1, ATF5, DUSP8, S100A6, and CHAC1. Importantly, shRNA-mediated knockdown of BBC3 suppresses apoptosis induced by C17ORF58 loss of function, suggesting that BBC3 is a key downstream target negatively regulated by C17ORF58.

Altogether, our data suggest that C17ORF58 is an anti-apoptotic protein exerting its activity by suppressing BBC3-induced apoptosis, presenting a potential novel target for improving PTCL therapies.

No relevant conflicts of interest to declare.