Korean researchers have identified a key gene that worsens treatment outcomes and triggers chemotherapy resistance in acute lymphoblastic leukemia (ALL), the most common childhood cancer. The finding is expected to provide a major breakthrough in developing new customized treatment strategies for intractable high-risk patients who relapse and show resistance to existing chemotherapy drugs.
A team led by Professor Kim Hong-tae of the Department of Biological Sciences at the Ulsan National Institute of Science and Technology (UNIST), working with Professor Yoo Keon-hee of Samsung Medical Center and Professor Kim Yun-hak of Pusan National University School of Medicine, announced Monday that an analysis of patient genomic data proved for the first time worldwide that the 'ZNF184' gene paralyzes the DNA repair system of cancer cells and worsens the disease.
Acute lymphoblastic leukemia is a representative blood cancer characterized by a rapid increase in immature lymphocytes. While it has relatively good treatment outcomes among childhood cancers, some patients still experience relapse or show treatment resistance, often remaining intractable, despite recent advances in genetic testing technology. Uncovering the early stages of cancer cell development and the specific pathways of disease progression has long been a challenge in leukemia treatment.
To track how patient cancer cells respond to and evolve from DNA damage, the joint research team began a genomic analysis combining cutting-edge 'single-cell and bulk RNA sequencing data' and discovered the role of the ZNF184 gene.
When cells in our body suffer fatal damage in which both DNA strands are severed (DSB), they activate 'homologous recombination (HR),' a high-precision repair system. Under normal conditions, key repair proteins such as BRCA1 should gather at the damaged site to carry out repairs.
However, the research found that in leukemia cells where the ZNF184 gene is overexpressed, the gene rapidly moves to the damaged site and acts as a kind of 'repair-blocking brake' that fundamentally blocks repair proteins from accessing the area.
Furthermore, the team uncovered the detailed mechanism by which the ZNF184 protein directly binds with 'TRIM28,' a chromatin regulatory factor, disrupting the overall dynamics of chromatin structure within the cell. DNA is densely folded in the form of chromatin wound around histone proteins inside the cell nucleus. To repair damaged DNA, the chromatin must briefly loosen so that repair proteins can enter, but ZNF184 interferes with this process like a 'locked door.'
As a result, with precision repair disrupted, untreatable DNA damage accumulates within the cell, and cancer cells evolve to survive while carrying this damage, leading to a decline in patient survival rates (poor prognosis).
In actual patient data analysis, the overall survival rate of the patient group with ZNF184 overexpression was significantly lower. In particular, the gene showed a clear pattern as a dynamic biomarker that reflects disease progression: expression was very high at initial diagnosis, dropped sharply in the state of 'clinical remission' when cancer cells disappeared through treatment, and surged again when the disease 'relapsed.'
Through this discovery, the research team was able not only to screen high-risk patients but also, paradoxically, to present an optimal treatment strategy capable of precisely targeting cancer cells. Cancer cells whose homologous recombination function is paralyzed due to ZNF184 overexpression take on a vulnerability (BRCAness) similar to that of 'BRCA mutation cancers' seen in breast and ovarian cancers.
The team attacked this vulnerability using the principle of 'synthetic lethality,' in which a cell dies when two weaknesses overlap. When they administered 'Olaparib,' a PARP inhibitor that suppresses single-strand DNA damage repair, they confirmed that only leukemia cells with high ZNF184 were selectively killed. In particular, they demonstrated through experiments using actual patient-derived cells that the therapeutic synergy in killing cancer cells was maximized when 'Doxorubicin,' a standard chemotherapy drug commonly used in clinical settings, was administered in combination with Olaparib.
"This study holds great significance in that it secured a genetic indicator for screening high-risk leukemia patients in advance, while at the same time laying the cornerstone of safe, customized precision medicine that kills only cancer cells by targeting their weaknesses, thereby reducing damage to normal cells," the joint research team said. "It is expected to greatly contribute to the development of low-toxicity new drugs and treatments for patients with intractable leukemia."
Meanwhile, the study was conducted with support from the Ministry of Trade, Industry and Energy, Seoul National University, and the National Research Foundation of Korea. The research findings were officially published on the 10th in 'Nucleic Acids Research,' a renowned international journal published by Oxford University Press.
