Kohrogi Kensaku, Hino Shinjiro, Sakamoto Akihisa, Anan Kotaro, Takase Ryuta, Araki Hirotaka, Hino Yuko, Araki Kazutaka, Sato Tetsuya, Nakamura Kimitoshi, Nakao Mitsuyoshi
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, and.
Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Blood Adv. 2021 May 11;5(9):2305-2318. doi: 10.1182/bloodadvances.2020003521.
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.
急性髓系白血病（AML）是一种异质性恶性肿瘤，其特征在于不同的谱系亚型以及各种基因/表观遗传改变。与其他肿瘤一样，AML细胞具有众所周知的有氧糖酵解现象，但也存在取决于细胞谱系的代谢差异。据报道，赖氨酸特异性去甲基化酶1（LSD1）对人类白血病发生至关重要，它目前是新兴的治疗靶点之一。然而，LSD1的代谢作用以及谱系依赖性因素在AML细胞中仍有待阐明。在此，我们表明LSD1在AML亚型中指导造血谱系特异性代谢程序。红白血病（EL）细胞在AML细胞系和临床样本中均特别表现出糖酵解激活和LSD1高表达。转录组、染色质免疫沉淀测序和代谢组分析表明，LSD1不仅对糖酵解至关重要，而且对血红素合成也至关重要，血红素合成是红系起源最具特征性的代谢途径。值得注意的是，LSD1稳定了红系转录因子GATA1，后者直接增强了糖酵解和血红素合成基因的表达。相反，LSD1通过表观遗传方式下调粒-单核细胞转录因子C/EBPα。因此，在EL细胞中使用LSD1敲低或化学抑制剂主要影响C/EBPα而非GATA1，导致代谢转变和生长停滞。此外，GATA1抑制编码C/EBPα的基因，而C/EBPα随后充当GATA1靶基因的阻遏物。我们共同得出结论，LSD1通过平衡这些谱系特异性转录因子塑造EL细胞中的代谢表型，并且LSD1抑制剂在药理学上会导致谱系依赖性代谢重塑。
