Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition

Dr. Chen, Liuh-Yow - May, 2024

Identifcation of cancer vulnerabilities through understanding the mechanism of ALT telomere maintenance

Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2, and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how the telomeric association of orphan NRs is involved in ALT activation remains unclear.

Dr. Liuh-Yow Chen at the Institute of Molecular Biology revealed that telomeric association of orphan NRs mediates ALT activation by triggering the formation of ALT-associated PML bodies (APBs). Using human fibroblasts as a model, the study found that the tethering of orphan NRs to telomeres induces APB formation and ALT activity, promoting telomere recombination. Orphan NRs initiate ALT via the zinc finger protein 827 and cooperate with deficiencies in the ALT suppressor ATRX-DAXX complex to promote ALT activation. Importantly, targeting APBs by depleting PML using arsenic trioxide (As2O3), a treatment for acute promyelocytic leukemia, abolished APB formation and ALT activity in cultured ALT cancer cells and ALT cancer cell line-derived mouse xenografts. This suggests the potential for further therapeutic development of As2O3 in treating ALT cancers, including pediatric brain tumors and sarcomas.

The study was published in Nucleic Acids Research on May 17, 2024. The first author of the paper is Venus Marie Gaela, a PhD student in TIGP-MCB at Academia Sinica. The research was supported by Academia Sinica and the National Science and Technology Council.