Researchers Uncover Mechanisms That Produce Individualized Metabolism in Leukemia

A research collaboration based at the University of Kumamoto (Japan) has shown that lysine-specific demethylase 1 (LSD1), an enzyme involved in gene expression, produces an individualized metabolism depending on the type of leukemia cells acute myeloid. Cancer cells are known to have a unique ability to metabolize substances differently from normal cells, and this ability is seen as a promising therapeutic target. New research results may contribute to the safe and effective use of LSD1 inhibitors as potential anticancer agents, and to the development of highly specific treatments for various types of leukemia.

Acute myeloid leukemia (AML) occurs when hematopoietic stem cells grow into tumors instead of differentiating into white or red blood cells. The different types of AML change depending on the stage of differentiation at which they become cancerous. Those that develop upon differentiation into red blood cells are classified as erythroblastic leukemia (ER). Although pathology-specific targeted molecular therapies have been developed for some forms of AML and have improved treatment outcomes, many forms of the disease, including LE, have high death rates due to the lack of therapies. individualized. Thus, therapies based on the type of disease and molecular pathology are desired.

Recent studies have found that the inherent metabolic capacity of cancer cells significantly contributes to tumor formation, metastasis, and resistance to treatment. Therefore, therapeutic strategies targeting nutrient transport and active metabolic pathways in cancer cells have been devised, but it has also been pointed out that metabolic characteristics vary depending on the type and progression of the cancer. The metabolic characteristics of AML have not been fully investigated and, in particular, the differences which depend on the type of disease and their mechanisms have not been clarified.

The expression of genes is regulated by the epigenome. Chemical changes, such as DNA methylation and the methylation of the histone proteins around which DNA wraps, act as markers to shape the epigenome. There are many differences in the epigenome between cancer cells and normal cells, which in turn generate differences in gene expression patterns.

Previously, the Kumamoto University research collaboration 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, not much is known about the differences in effectiveness by type of disease. So, in this study, the researchers decided to focus on the metabolic differences depending on the type of AML disease and the role of LSD1.

They first analyzed the gene expression database of patients with AML and cultured cell lines derived from AML, and found that the LSD1 and glycolytic genes are highly expressed in LE in patients with AML. . Then, when they tested the inhibition of LSD1 function using EL cell lines, they found that LSD1 promotes uptake of glucose into cells and the glycolytic system. Integrated omics analysis revealed that heme synthesis, a metabolic pathway characteristic of normal red blood cells, is also activated by LSD1. The mechanism has been shown that LSD1 activates the expression of glycolytic and heme synthetic genes by preventing the degradation of the protein GATA1, an erythroid transcription factor.

In addition, under functional inhibition of LSD1, the expression of CEBP / α, a transcription factor of the granulocyte-monocyte line of leukocytes, was considerably upregulated, inhibiting metabolic regulation by GATA1. These results indicate that LSD1 regulates the balance of transcription factors involved in the hematopoietic cell line, thereby generating the metabolic phenotype characteristic of EL. In addition, analysis of clinical data covering various forms of AML showed that expression of the synthetic LSD1, GATA1 and glycolytic genes and heme exhibited a significant positive correlation. This suggests that regulation of the cell line by LSD1 may generate the diversity of metabolic types of AML.

“Based on our research, a combination of LSD1 inhibitors, metabolic target drugs, and conventional therapies can be very effective in treating EL patients who express high levels of LSD1,” said Associate Professor Shinjiro Hino, who led the study. “It can also be an important clue in selecting patients who might benefit from LSD1 inhibitors in clinical trials.”