The results of a study led by Dr. Shujun Liu, head of the Cancer Epigenetics and Experimental Therapeutics lab at The Hormel Institute, were published in the high impact journal Nature Communications this week. The research, led by Dr. Liu and team, showed a significant new understanding about what causes the spread of leukemia at the molecular level. Leukemogenesis is mediated by a fusion oncogenic protein AML1-ETO resulting from the translocation of chromosome 8 and chromosome 21. Dr. Liu’s study shows the enhancer of zeste homolog 1 (EZH1), a histone lysine methyltransferase, posttranslationally modifies non-histone protein AML1-ETO, resulting in further silencing of tumor suppressor genes leading to more aggressive cancer growth.
The article, “Protein Lysine 43 Methylation by EZH1 Promotes AML1-ETO Transcriptional Repression in Leukemia” was a collaboration with other researchers from Chinese PLA General Hospital, Jilin University, Mayo Clinic, City of Hope and Shenzhen University, including Drs. Liping Dou, Fei Yan, Jiuxia Pang, Dehua Zheng, Dandan Li, Li Gao, Lijun Wang, Yihan Xu, Jinlong Shi, Qian Wang, Lei Zhou, Na Shen, Puja Singh, Lili Wang, Yonghui Li, Yvchi Gao, Tao Liu, Chongjian Chen, Aref Al-Kali, Mark R. Litzow, Young-In Chi, Ann M. Bode, Chunhui Liu, Haojie Huang, Daihong Liu, Guido Marcucci, Li Yu.
Although AML1-ETO-positive leukemia is often referred as having a favorable prognosis, more than 40% of patients may relapse and die without curative regimens available. While seen less frequently, lysine methylation on non-histone proteins emerges as an important regulator of cancer. EZH1 is a well-known oncogene, but most findings are in histone field. To date, all results from previous studies believe that EZH1 is only a histone lysine methyltransferase.
Therapies remain difficult because treating chimeric oncoproteins such as AML1-ETO remains low, these discoveries may lead to new approaches to design drugs to specifically break AML1-ETO-EZH1 protein interaction, thus disrupting AML1-ETO’s oncogenic functions and limiting leukemia progression.
Approximately every 3 minutes one person in the United States (USA) is diagnosed with a blood cancer. An estimated combined total of 176,200 people in USA are expected to be diagnosed with leukemia, lymphoma or myeloma in 2019, which accounts for more than 10 percent of the estimated 1,762,450 new cancer cases this year (news from Leukemia and Lymphoma Society). Leukemia is a fatal disease for most patients. Because the molecular causes of leukemia are not fully known, effective therapeutic interventions are lacking. Further, EZH1 is an oncogenic protein for many types of cancers. The findings by Dr. Liu and his team provide mechanism-based therapeutic options to cure not only lethal blood cancer, but also other cancers.