Understanding the Implications of EP300 deficiency in Adult T-Cell Leukemia/Lymphoma

Adult T-cell Leukemia/Lymphoma (ATLL) is an aggressive T-cell malignancy caused by Human T-cell Lymphotropic Virus Type-1 (HTLV-1) infection. HTLV-1 is endemic to Japan, the Caribbean basin, South America, Eastern Europe and certain areas of Africa. Due to population migration from the Caribbean basin, and South America, there are increasing ATLL patients being treated in the United States. North American ATLL patients (NA-ATLL) exhibit chemo-refractory disease with an overall survival (OS) of only 6.9 months, compared to other ATLL patients (OS of ~1 year). There are currently no effective therapies for ATLL, including the most aggressive forms seen in NA-ATLL. There is an urgent need to understand the mechanisms contributing to severe disease presentation in NA-ATLL to identify new therapeutic targets that could improve overall survival for these patients. A recent study has revealed significant differences in the transcriptional and epigenetic landscape between NA-ATLL and other ATLL patients. In particular, somatic loss-of-function mutations in the E1A binding protein (EP300) have been identified in 20% of NA-ATLL patients. EP300 and its homology CREBB binding protein (CBP), often studied together due to overlapping roles, are major transcriptional co-activators and lysine acetyl transferases. However, genome-wide ChIP-seq studies have revealed distinct binding sites for each protein, indicating that these two proteins may have unique functions in the cell. Our research taking advantage of a unique collection of EP300Mut ATLL cells and an innovative EP300-specific PROTAC degrader shows that reduced EP300 activity is linked to severe dysregulations in DNA replication dynamics, characterized by defective replication fork protection, and the accumulation of cytosolic DNA, which induces cellular toxicity. Moreover, pilot studies show that reduced EP300 is associated with mitochondrial dysfunction and increased oxidative stress. Therefore, the goals of this project are to dissect the mechanisms promoting replicative abnormalities, DNA damage induction and tolerance, in order to identify novel therapeutic strategies for NA- ATLL. In the short term, the knowledge gleaned from these investigations will significantly advance our understanding of NA-ATLL pathophysiology and clarify the mechanistic role of EP300 in the disease. In the long term, we envision that these results will pave the way for leveraging the identified vulnerabilities as therapeutic strategies for NA-ATLL. Project Number: 1R01CA307099-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Advaitha Madireddy | Institution: RUTGERS BIOMEDICAL AND HEALTH SCIENCES, Newark, NJ | Award Amount: $672,960 | Activity Code: R01 | Study Section: Biochemical and Cellular Oncogenesis Study Section[BCO] View on NIH RePORTER: https://reporter.nih.gov/project-details/11270067