Researchers elucidate the mechanisms that produce individual metabolism in leukemia

A collaborative study based at Kumamoto University (Japan) has shown that lysine-specific demethylase 1 (LSD1), an enzyme involved in gene expression, induces individual metabolism depending on the type of acute myeloid leukemia cell. I did. Cancer cells are known to have a unique ability to metabolize substances different from normal cells, and this ability is considered to be a promising therapeutic target. New findings may contribute to the safe and effective use of LSD1 inhibitors as potential anti-cancer agents and the development of highly specific therapies for various leukemia types.

Acute myeloid leukemia (AML) occurs when hematopoietic stem cells become tumors rather than differentiate into white blood cells or red blood cells. Different types of AML develop depending on at what stage of differentiation they become cancerous. Those that develop when they differentiate into red blood cells are classified as erythroblastic leukemia (EL). Pathology-specific targeted molecular therapies have been developed for several forms of AML and improved outcomes, but many forms of disease, including EL, are highly mortal due to the lack of individualized therapies. Shows the rate. Therefore, a treatment method based on the type of disease and molecular pathology is desired.

Recent studies have shown that the unique metabolic capacity of cancer cells contributes significantly to tumor formation, metastasis, and resistance to treatment. Therefore, therapeutic strategies targeting active nutrient transport and metabolic pathways in cancer cells have been devised, but it has also been pointed out that metabolic characteristics differ depending on the type and progression of cancer. The metabolic properties of AML have not been thoroughly investigated, and in particular, differences that depend on the type of disease and its mechanism have not been clarified.

Gene expression is regulated By the epigenome. Chemical modifications such as DNA methylation and methylation of the histone proteins that DNA encloses serve as markers for the formation of the epigenome. There are many differences in the epigenome between cancer cells and normal cells, which make up differences in gene expression patterns.

Previously, a collaborative study at Kumamoto University showed that LSD1, a demethylase that removes methyl groups from methylated histones, is involved in the regulation of energy metabolism in various cell types (Nature Communications 2012, Cancer Research 2015, Nucleic Acids Research 2018). Therefore, they decided to test the possibility that LSD1 is involved in the metabolic regulation of AML cells. Although LSD1 inhibitors have been shown to be effective in treating AML, Effectiveness It depends on the type of illness. Therefore, in this study, researchers decided to focus on metabolic differences depending on the type of AML disease and the role of LSD1.

They first analyzed the gene expression databases of AML patients and cultured cell lines derived from AML and found that both LSD1 and glycolytic genes were highly expressed in EL in AML patients. Next, we tested inhibition of LSD1 function using EL cell lines and found that LSD1 promoted glucose uptake into cells and glycolysis. Integrated omics analysis revealed that heme synthesis, a characteristic metabolic pathway of normal red blood cells, is also activated by LSD1. It was found that this mechanism activates the expression of glycolysis and heme synthesis genes by preventing the degradation of the GATA1 protein, which is an erythrocyte transcription factor, by LSD1.

Furthermore, under the functional inhibition of LSD1, the expression of CEBP / α, a transcription factor of leukocyte granulocyte-monocyte lineage, was dramatically up-regulated, and the metabolic regulation by GATA1 was inhibited. These results indicate that LSD1 regulates the balance of transcription factors involved in hematopoietic cell lines, thereby producing the metabolic phenotype characteristic of EL. In addition, analysis of clinical data covering various forms of AML showed that expression of LSD1, GATA1, glycolysis and heme synthesis genes showed a significant positive correlation. This suggests that the regulation of cell lineage by LSD1 may produce a metabotropic diversity of AML.

“Our study shows that a combination of LSD1 inhibitors, metabolic targets, and conventional treatments can be very effective in treating EL patients who express high levels of LSD1.” Said Associate Professor Shinjiro Hino, who led the study. “It may also be an important clue in selecting patients who may benefit from LSD1 inhibitors in clinical trials.”