Adult T-cell leukemia/lymphoma (ATLL) is a fatal cancer that disproportionately affects the Bronx’s immigrant population. In a December 7, 2025, Nature Communications paper, B. Hilda Ye, Ph.D., and colleagues describe how mutations in EP300, a regulator of gene activity, contribute to ATLL and similar cancers.

Cells with missing or defective EP300 experience chronic “replication stress,” meaning they struggle to accurately copy their DNA before dividing. As a result EP300-deficient cells accumulate significant DNA damage. The researchers discovered that EP300 plays a crucial role in protecting “replication forks”—the active and vulnerable structures where DNA duplication occurs.

When a replication fork stalls, protective proteins such as BRCA2 normally preserve genomic stability by maintaining fork integrity and preventing newly synthesized DNA from being degraded by nucleases. BRCA2 is well known as a “cancer gene,” because inheriting BRCA2 mutations greatly increases risk for breast and ovarian cancers. Insufficient BRCA2 protein causes replication forks to collapse, leading to chromosome damage and mutations.

The investigators found that in ATLL cells, loss of EP300 creates a BRCA2-like defect. Although the BRCA2 gene itself is not mutated in ATLL, BRCA2 protein levels drop, fork protection fails, and gaps in single-stranded DNA accumulate, leading to a phenotype similar to BRCA2-deficient cancers. Those cancers are vulnerable to PARP inhibitors and similar drugs that work by exploiting malignant cells’ weakened DNA repair capacity. Importantly, Dr. Ye and colleagues showed that EP300-mutant cells share this therapeutic vulnerability, suggesting a new targeted treatment strategy for ATLL and other cancers carrying EP300 mutations.

Dr. Ye, a professor of cell biology at Albert Einstein College of Medicine and a member of the Montefiore Einstein Comprehensive Cancer Center, is senior author. Advaitha Madireddy, Ph.D., at Rutgers Cancer Institute of New Jersey, is the corresponding author. Additional authors are from St. Jude Comprehensive Cancer Center and Dana-Farber Cancer Institute.