Leukemia, a type of blood cancer, affected around 2.3 million people around the world in 2015. Acute myeloid leukemia (AML)—a particularly aggressive disease—generally starts in the bone marrow, when stem cells cannot differentiate into white blood cells, which reduces the number of healthy blood cells in the body, leading to a very weak immune system, among other problems. Given the prevalence and implications of this disease, there has been a lot of research on the development and progression of leukemia. This has led to the discovery of a protein, stimulator of interferon genes (STING), which interacts with two other proteins—TANK-binding kinase 1 (TBK1) and signal transducer and activator of transcription 6 (STAT6)—to exert anti-cancer effects in blood cancers. Researchers have also observed that a particular gene—surfeit 4 (SURF4)—is highly expressed in leukemic cells, and its protein, SURF4, binds to STING. However, we are still unclear about how SURF4 affects the STING-TBK1-STAT6 axis, and what role it plays in leukemia. So, a team of researchers from Pusan National University, Republic of Korea set out to understand this. They were led by Professors Dongjun Lee and Yun Hak Kim, who explain the rather humanitarian motive for their research. "Children who suffer from AML relapses seldom survive. This makes studying the mechanisms of AML very important. Uncovering the effects of proteins like SURF4 may lead to new therapeutic strategies for AML, which hasn't happened in four decades". The team ran a series of experiments, the findings of which are detailed in a letter to the editor, published on 6 November 2022 in Cancer Communications.
First, using multiple short hairpin RNA constructs to target SURF4, the team suppressed its expression in myeloid leukemic cells and compared these to control leukemic cells. The former showed increased cell differentiation, cell death, and accumulation of ROS. Tumors containing these cells also displayed arrested growth when inoculated in mice. The researchers additionally compared SURF4 expression levels among patients with AML and saw that patients with higher SURF4 expression levels had significantly shorter survival. It was also observed that SURF4 expression was much higher in patients suffering from AML compared to healthy people. These observations suggest that SURF4 regulates cell death and differentiation in AML. Interestingly, SURF4 silencing did not affect the cell cycle status.
"Our research shows the role played by SURF4 in myeloid leukemia. It negatively regulates the STING-TBK1-STAT6 axis and inhibits the death of cancer cells. We also found that depletion of SURF4 synergistically works with anti-cancer drugs to reduce myeloid leukemic cell burden," says Prof. Lee.
"Therefore," Prof. Kim concludes, "inhibiting SURF4 expression using monoclonal antibodies and/or aptamers may present a better alternative to current cancer therapies that wipe out the immune system and have multiple side effects. This is a promising option for the treatment of hematological cancers."
Overall, their findings have increased our understanding of AML and have opened new avenues for the treatment of not only AML but also other blood cancers.
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Reference
DOI: https://doi.org/10.1002/cac2.12390
Authors: Jayoung Kim1, Hansong Lee2, Chae Mi Hong1, Ji Ho Nam3, Hye Ju Yeo4, Woo Hyun Cho4, Hyung-Sik Kim5, Changwan Hong6, Yun Hak Kim2,6, Dongjun Lee1
Affiliations:
1Department of Convergence Medicine, School of Medicine, Pusan National University
2Department of Biomedical Informatics, School of Medicine, Pusan National University
3 Department of Radiation Oncology, School of Medicine, Pusan National University
4 Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Internal Medicine, Pusan National University Yangsan Hospital
5 Department of Oral Pathology, Dental and Life Science Institute, School of Dentistry, Pusan National University
6 Department of Anatomy, School of Medicine, Pusan National University
About Pusan National University
Pusan National University, located in Busan, South Korea, was founded in 1946 and is now the no. 1 national university of South Korea in research and educational competency. The multi-campus university also has other smaller campuses in Yangsan, Miryang, and Ami. The university prides itself on the principles of truth, freedom, and service, and has approximately 30,000 students, 1200 professors, and 750 faculty members. The university is composed of 14 colleges (schools) and one independent division, with 103 departments in all.
Website: https://www.pusan.ac.kr/eng/Main.do
About the authors
Dr. Dongjun Lee is an Associate Professor of the Department of Convergence Medicine at Pusan National University School of Medicine. His group is to define stem cell regulation and disease and how we can utilize information to develop novel therapies. Lee group is also interested in regenerative medicine, vascular biology, cancer, and stem cell biology, with a particular focus on translational medicine. Before coming to Pusan National University School of Medicine, he completed Postdoctoral training at David Scadden's lab at the Center for Regenerative medicine (CRM) at Harvard University and Massachusetts General Hospital. In 2010, Dongjun Lee received a Ph.D. in the Department of Biological Sciences from the Korea Advanced Institute of Sciences and Technology (KAIST).
Lab website: https://leelab.wixsite.com/leelab
ORCID id: 0000-0001-6828-401X
Dr. Yun Hak Kim is an Associate Professor at the Department of Anatomy & Department of Biomedical Informatics at Pusan National University. In 2016, Yun Hak Kim received a Ph.D. in pharmacology lab from Pusan National University. He also completed Postdoctoral training at the Department of Anatomy at Pusan National University. His research group's major focus is the development of new biomarkers for several diseases using genomic big data and validating these biomarkers.
Lab website: https://yunhakkim.pusan.ac.kr
ORCID id: 0000-0002-9796-8266
