Epigenetic drug library screening identified an LSD1 inhibitor to target UTX-deficient cells for differentiation therapy

• Published in: Signal transduction and targeted therapy 2019-04, Vol.4 (1), p.11-11, Article 11
• Main Authors: Wu, Baohong, Pan, Xiangyu, Chen, Xuelan, Chen, Mei, Shi, Kaidou, Xu, Jing, Zheng, Jianan, Niu, Ting, Chen, Chong, Shuai, Xiao, Liu, Yu
• Format: Article
• Language: English
• Subjects: 631/67; 692/4028/67; Cancer Research; Cell Biology; Cell self-renewal; Epigenetics; Gene expression; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Pathology
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-019-0040-2

UTX (also known as KDM6A), a histone 3 lysine 27 demethylase, is among the most frequently mutated epigenetic regulators in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Recent studies have suggested that UTX mutations promote MDS and AML by blocking the differentiation of hematopoietic stem and progenitor cells (HSPCs). Here, we performed an epigenetic drug library screening for small molecules able to release the differentiation block on HSPCs induced by UTX deficiency. We found that SP2509, a selective inhibitor of LSD1, specifically promoted the differentiation of Utx -null HSPCs while sparing wild-type HSPCs. Transcriptome profiling showed that Utx loss reduced the expression of differentiation-related and tumor suppressor genes, correlating with their potential roles in HSPC self-renewal and leukemogenesis. In contrast, SP2509 treatment reversed these changes in gene expression in Utx -null HSPCs. Accordingly, Utx loss decreased H3K4 methylation level probably through the COMPASS-like complex, while LSD1 inhibition by SP2509 partially reversed the reduction of H3K4 methylation in Utx -deficient HSPCs. Further, SP2509 promoted the differentiation of Utx -null AML cells in vitro and in vivo and, therefore, extended the survival of these leukemic mice. Thus, our study identified a novel strategy to specifically target both premalignant and malignant cells with Utx deficiency for differentiation therapy and provided insights into the molecular mechanisms underlying the role of Utx in regulating HSPCs and related diseases. Cancer: Restoring differentiation A small molecule that restores the differentiation of hematopoietic stem and progenitor cells (HSPCs) extends the survival of mice with leukemia. Mutations that impair the activity of UTX, a protein that mediates heritable changes in gene expression by removing methyl groups from histones, prevent the production of blood cells in the bone marrow and have been associated with leukemia. Yu Liu and colleagues at Sichuan University, China, carried out a screen for compounds that target epigenetic regulators and found that SP2509, an LSD1 inhibitor, promoted HSPC differentiation and tumor suppressor gene expression in cells lacking UTX activity. The ability of SP2509 to stop the progression of leukemia in mice suggests that it could be a potential treatment strategy for cancers driven by UTX mutations.