LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα

Abstract

Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by distinct lineage subtypes and various genetic/epigenetic alterations. As with other neoplasms, AML cells have well-known aerobic glycolysis, but metabolic variations depending on cellular lineages also exist. Lysine-specific demethylase-1 (LSD1) has been reported to be crucial for human leukemogenesis, which is currently one of the emerging therapeutic targets. However, metabolic roles of LSD1 and lineage-dependent factors remain to be elucidated in AML cells. Here, we show that LSD1 directs a hematopoietic lineage-specific metabolic program in AML subtypes. Erythroid leukemia (EL) cells particularly showed activated glycolysis and high expression of LSD1 in both AML cell lines and clinical samples. Transcriptome, chromatin immunoprecipitation–sequencing, and metabolomic analyses revealed that LSD1 was essential not only for glycolysis but also for heme synthesis, the most characteristic metabolic pathway of erythroid origin. Notably, LSD1 stabilized the erythroid transcription factor GATA1, which directly enhanced the expression of glycolysis and heme synthesis genes. In contrast, LSD1 epigenetically downregulated the granulo-monocytic transcription factor C/EBPα. Thus, the use of LSD1 knockdown or chemical inhibitor dominated C/EBPα instead of GATA1 in EL cells, resulting in metabolic shifts and growth arrest. Furthermore, GATA1 suppressed the gene encoding C/EBPα that then acted as a repressor of GATA1 target genes. Collectively, we conclude that LSD1 shapes metabolic phenotypes in EL cells by balancing these lineage-specific transcription factors and that LSD1 inhibitors pharmacologically cause lineage-dependent metabolic remodeling.

Differentiation and prognostic stratification of acute myeloid leukemia by serum‐based spectroscopy coupling with metabolic fingerprints

“…The above SERS results further confirmed that metabolisms of these aromatic amino acids could be involved in anaplerosis, and together with glycine in glycine, serine and threonine metabolism for further involvement in arginine and proline metabolism 35,36 . Accumulating data from SERS and NMR suggested genetic abnormality as major determinant of AML prognostic characteristics, and several reports have recently highlighted the role of specific mutations in metabolic features 37,38 . Thus, lineage identity and genetic mutations may cooperatively direct metabolic reprogramming that allows AML to be divided into risk subgroups based on their characteristics of karyotypes.…”

“…35,36 Accumulating data from SERS and NMR suggested genetic abnormality as major determinant of AML prognostic characteristics, and several reports have recently highlighted the role of specific mutations in metabolic features. 37,38 Thus, lineage identity and genetic mutations may cooperatively direct metabolic reprogramming that allows AML to be divided into risk subgroups based on their characteristics of karyotypes. We may propose that AML subjects were typically accompanied by amino acids and nucleotides metabolisms and may progress to very different prognostic outcome with certain molecular events.…”

Lysine-Specific Demethylase 1 (LSD1/KDM1A) Inhibition as a Target for Disease Modification in Myelofibrosis

“…The improvement in hemoglobin is an intriguing observation and is likely to address the issue of anemia associated with ruxolitinib. A possible explanation for this observation is that the modulation of transcription by LSD1 is lineage-specific or that expression of the γ-globin gene is altered with LSD1 inhibition [86,87]. Eighty-five percent of patients had stable or improved fibrosis score of at least one grade.…”

One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies

“…In the second step of glucose metabolism, previous studies in leukaemia have described miR-15a and miR-16-1 as targeting the aldolase A (ALDOA), which converts fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate in the glycolysis pathway [ 322 ] ( Figure 2 ). Connecting glucose uptake indirectly to activation of epigenetic enzymes with dual activity, in AML, LSD1 stabilises the transcription factor GATA1 on protein level and epigenetically silences the GATA1 negative regulator C/EBPα, thus promoting glucose metabolism [ 323 ]. In haematological malignancies, e.g., AML, MDS, and CML, LSD1 contributes to leukaemogenesis [ 324 ].…”