New Study Unveils Genetic Marker Linked to Treatment Response and Relapse in Pediatric Leukemia
UNIST, Samsung Medical Center, and Pusan National University Uncover How ZNF184 Impairs DNA Repair and Drives Disease Progression.
JooHyeon Heo
Abstract Zinc finger proteins (ZNFs) are increasingly recognized as regulators of oncogenic transcriptional networks and DNA damage responses. Through integrative analysis of bulk and single-cell RNA sequencing data, we identified a conserved set of seven ZNF genes, including ZNF184, that are upregulated in acute lymphoblastic leukemia (ALL) and exhibit dynamic expression patterns linked to disease progression. Among these, ZNF184 uniquely localized to DNA double-strand breaks (DSBs) in a zinc finger domain-dependent manner. Functional analyzes revealed that ZNF184 suppresses homologous recombination (HR)-mediated DNA repair by impeding BRCA1 recruitment, leading to accumulation of DNA damage. ZNF184 expression was elevated in primary ALL samples and associated with increased γH2AX levels and inferior overall survival in ALL patients. Loss of ZNF184 restored HR efficiency, reduced DNA damage burden, and enhanced genome stability, while re-expression re-sensitized cells to DNA-damaging agents. Mechanistically, ZNF184 directly interacted with TRIM28 and facilitated its recruitment to DSBs, modulating TRIM28 phosphorylation and chromatin remodeling through the HP1/SUV39H1 complex. ZNF184 expression conferred heightened sensitivity to PARP inhibition and synergized with genotoxic chemotherapy in both cell lines and patient-derived ALL cells. These findings identify ZNF184 as a key modulator of DSB repair and a predictive biomarker for therapeutic strategies targeting HR-deficient ALL. A joint team from UNIST, Samsung Medical Center, and Pusan National University (PNU) has identified a gene that influences treatment outcomes and relapse in childhood leukemia, specifically acute lymphoblastic leukemia (ALL). Led by Professor Hongtae Kim from the Department of Biological Sciences at UNIST, Professor Keon Hee Yoo from Samsung Medical Center, Professor Yun Hak Kim from the School of Medicine of Pusan National University, their research uncovers new potential targets for overcoming drug resistance and preventing recurrence. ALL is the most common childhood cancer, with most patients responding well to therapy. However, some experience relapse or develop resistance, leading to poorer prognoses. The researchers investigated how differences in the cells' DNA repair mechanisms might explain these variations. Their analysis of patient genomic data highlighted ZNF184 as a key player. Elevated ZNF184 levels weaken the cell's ability to repair double-strand DNA breaks through homologous recombination—the process responsible for precise DNA repair. When HR is disrupted, DNA damage accumulates, allowing cancer cells to survive despite treatment. Patients with high ZNF184 expression showed lower survival rates, and the gene's activity fluctuated with disease status—peaking at diagnosis and relapse and falling during remission. Further experiments revealed ZNF184 localizes to damaged DNA sites and interacts with TRIM28, affecting chromatin structure and impeding repair. The team demonstrated that targeting this vulnerability enhances treatment efficacy. Combining PARP inhibitors—already used in other cancers—with conventional chemotherapy significantly increased leukemia cell death, especially in cells with high ZNF184 expression. This research suggests that measuring ZNF184 levels could help identify high-risk patients and tailor more effective treatments. By exploiting the specific weaknesses caused by ZNF184 overexpression, doctors may improve outcomes while minimizing side effects. Professor Hongtae Kim, lead author and professor at UNIST, remarked, “Understanding how ZNF184 disrupts DNA repair pathways opens new avenues for treating resistant leukemia. Targeted therapies that exploit these vulnerabilities could transform outcomes for high-risk children.” Supported by the Ministry of Trade, Industry & Energy (MOTIE), Seoul National University (SNU), and the National Research Foundation of Korea (NRF), the full research appears in Nucleic Acids Research on June 10, 2026. Journal Reference Won Chan Hwang, Hee Young Ju, Kibeom Park, et al ., "ZNF184 negatively regulates HR repair and predicts poor prognosis in acute lymphoblastic leukemia", Nucleic Acids Res., (2026).