Shanghai Institute of Hematology / State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine ) The latest research results on the molecular mechanism of treatment of acute promyelocytic leukemia (APL), the study revealed that the oncoprotein PML-RAR is a direct drug target for arsenic treatment of APL. They found that arsenic trioxide directly binds to the cysteine ​​in the "zinc finger" structure of the PML end of the oncoprotein, which induces conformational changes and multimerization of the protein, followed by SUMOylation and ubiquitination modification and degradation by the proteasome. The degradation of oncoproteins eventually leads to the differentiation and apoptosis of leukemia cells. Make APL a successful example of clinical cure of human acute leukemia molecular targeted therapy.
This achievement enriches the theory of APL targeted therapy, and is also of great guiding significance for promoting the research of molecular targeted therapy of other types of leukemia and solid tumors. The breakthrough made by this institute is the result of sincere cooperation and joint research with many units such as the Institute of Biochemical Cells and Drugs, Chinese Academy of Sciences and Shanghai Institute of Biological Sciences, the Hefei National Synchrotron Radiation Laboratory and the School of Life Sciences, University of Science and Technology of China.
APL is a special type of acute myeloid leukemia with the characteristic PML-RAR oncoprotein. APL was once considered to be one of the most dangerous leukemias, and many patients died of severe bleeding early in the onset of the disease and lacked effective treatment. In 1985, Professor Wang Zhenyi of Shanghai Institute of Hematology took the lead in the international application of all-trans retinoic acid (ATRA) in the treatment of APL patients. More than 80% of patients could be completely remitted, but they are prone to relapse in the short term. In the 1990s, based on the application of traditional Chinese medicine arsenic trioxide in the treatment of APL patients by Professor Zhang Tingdong of Harbin Medical University and other researchers, Chen Zhu and Chen Saijuan of Shanghai Blood Research Institute successfully used arsenic trioxide to treat patients with relapsed all-trans retinoic acid resistance. And found a dual pharmacological mechanism of arsenic agent induced leukemia cell differentiation and apoptosis. After further clinical practice, they proved that the combined application of all-trans retinoic acid and arsenic trioxide can achieve about 5 years of disease-free survival of about 90% of APL patients, and no obvious long-term toxic effects have been seen, thus making APL the first basically curable. Acute myeloid leukemia. "Tracing back to the source", revealing the scientific nature of clinical phenomena, and explaining the molecular targets and mechanisms of drugs are of great significance for understanding the pathogenesis of malignant tumors and exploring innovations in treatment theories. All-trans retinoic acid, by targeting to the retinoic acid receptor (RAR) domain of the oncoprotein PML-RAR, restarts the differentiation gene regulatory network of myeloid cells, and induces leukemia cells to differentiate and mature and then to apoptosis. But the question that has puzzled researchers for a long time is: What is the direct molecular target and molecular mechanism of arsenic trioxide?
Based on the analysis of the previous research results and sensitivity to important scientific issues, Chen Zhu and Chen Saijuan first proposed that arsenic is likely to directly target the PML-RAR oncoprotein and play a specific therapeutic role. The first problem to be solved in the study of drug molecular targets is to label and trace drugs. Arsenic trioxide is a small molecule inorganic compound that is difficult to label. The researchers cleverly used two organic arsenic-one is labeled with biotin, and the other can emit a red fluorescent signal after binding to the adjacent sulfhydryl group of the protein, confirming that the arsenic agent can directly bind to the cancer protein PML- in the cell. RAR, while unlabeled arsenic trioxide can competitively inhibit this binding. Further tracking will locate the binding site of arsenic to the PML domain on the oncoprotein. Subsequently, the researchers used biotechnology to synthesize PML domain proteins, and various mass spectrometry and spectroscopy analysis confirmed that arsenic was bound to the PML domain by forming an arsenic-sulfur coordination covalent bond with cysteine. They also collaborated with other research groups to analyze the coordination pattern and local structure of arsenic and PML protein binding by means of structural biology and biophysics. The PML part of the PML-RAR oncoprotein contains a zinc finger domain, which binds to zinc under physiological conditions. The researchers found that arsenic can competitively replace the combination of zinc and protein at higher concentrations through nuclear magnetic resonance technology. Next, they analyzed how the binding of arsenic determines the fate of the oncoprotein. Through experiments inside and outside the cell, it was found that the arsenic agent combined with the PML domain induced protein conformation changes and multimerization, which promoted its interaction with a The enhanced interaction between the post-translational modification enzyme UBC9 makes cancer protein more easily modified by a ubiquitin-like protein SUMO, which in turn undergoes ubiquitination modification and is degraded by the proteasome. The degradation of oncoproteins eventually leads to the differentiation and apoptosis of leukemia cells. Make APL a successful example of clinical cure of human acute leukemia molecular targeted therapy.
This research result not only explains the molecular target and molecular mechanism of arsenic trioxide in the treatment of APL, but its more profound significance lies in: first, all-trans retinoic acid and arsenic agents target and bind to different regions of the same cancer protein. It plays a synergistic role and induces leukemia cell differentiation and apoptosis, which provides a theoretical and practical basis for a new strategy for cancer treatment. Second, arsenic is an ancient Chinese medicine with a history of more than 2,000 years. Using modern scientific methods to reveal the molecular mechanism of Chinese medicine will promote the in-depth exploration and excavation of the traditional medical treasure house of the motherland by Chinese scientists. Thirdly, this research result is the result of the integration and intersection of multi-disciplinary and multi-research fields, which opens up new ways for clinical scientific research. The research is based on the three-generation research team of the old, middle-aged and young people of the Shanghai Institute of Hematology. It has combined many domestic and foreign scientific research institutions, including the Institute of Biochemical Cells and Drugs, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Institute of High Energy Physics, Chinese Academy of Sciences, and School of Life Sciences, University of Science and Technology of China , Hefei National Synchrotron Radiation Laboratory, Institute of Zoology, Chinese Academy of Sciences, China-France Life Science and Genome Research Center, and the research team of many universities in Paris, France, sincere cooperation, joint research and breakthroughs. The research was supported by the National 863 Program, the 973 Program, the National Natural Science Foundation of China, and the Shanghai Major Science and Technology Special Fund.
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