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Super-enhancer profiling identifies novel critical and targetable cancer survival gene LYL1 in pediatric acute myeloid leukemia.
Fang, Fang; Lu, Jun; Sang, Xu; Tao, Yan-Fang; Wang, Jian-Wei; Zhang, Zi-Mu; Zhang, Yong-Ping; Li, Xiao-Lu; Xie, Yi; Wu, Shui-Yan; Chu, Xin-Ran; Li, Gen; Wu, Di; Chen, Yan-Ling; Yu, Juan-Juan; Jia, Si-Qi; Feng, Chen-Xi; Tian, Yuan-Yuan; Li, Zhi-Heng; Ling, Jing; Hu, Shao-Yan; Pan, Jian.
Afiliación
  • Fang F; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Lu J; Department of Hematology, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, Jiangsu, China.
  • Sang X; Department of Pediatrics, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, China.
  • Tao YF; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Wang JW; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Zhang ZM; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Zhang YP; Department of Hematology, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, Jiangsu, China.
  • Li XL; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Xie Y; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Wu SY; Intensive Care Unit, Children's Hospital of Soochow University, Suzhou, 215003, China.
  • Chu XR; Department of Hematology, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, Jiangsu, China.
  • Li G; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Wu D; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Chen YL; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Yu JJ; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Jia SQ; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Feng CX; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Tian YY; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Li ZH; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • Ling J; Department of Hematology, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, Jiangsu, China.
  • Hu SY; Department of Hematology, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, Jiangsu, China. hsy139@126.com.
  • Pan J; Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China. panjian2008@163.com.
J Exp Clin Cancer Res ; 41(1): 225, 2022 Jul 16.
Article en En | MEDLINE | ID: mdl-35842703
BACKGROUND: Acute myeloid leukemia (AML) is a myeloid neoplasm makes up 7.6% of hematopoietic malignancies. Super-enhancers (SEs) represent a special group of enhancers, which have been reported in multiple cell types. In this study, we explored super-enhancer profiling through ChIP-Seq analysis of AML samples and AML cell lines, followed by functional analysis. METHODS: ChIP-seq analysis for H3K27ac was performed in 11 AML samples, 7 T-ALL samples, 8 B-ALL samples, and in NB4 cell line. Genes and pathways affected by GNE-987 treatment were identified by gene expression analysis using RNA-seq. One of the genes associated with super-enhancer and affected by GNE-987 treatment was LYL1 basic helix-loop-helix family member (LYL1). shRNA mediated gene interference was used to down-regulate the expression of LYL1 in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. RESULTS: We identified a total of 200 genes which were commonly associated with super-enhancers in ≧10 AML samples, and were found enriched in regulation of transcription. Using the BRD4 inhibitor GNE-987, we assessed the dependence of AML cells on transcriptional activation for growth and found GNE-987 treatment predominantly inhibits cell growth in AML cells. Moreover, 20 candidate genes were selected by super-enhancer profile and gene expression profile and among which LYL1 was observed to promote cell growth and survival in human AML cells. CONCLUSIONS: In summary, we identified 200 common super-enhancer-associated genes in AML samples, and a series of those genes are cancer genes. We also found GNE-987 treatment downregulates the expression of super-enhancer-associated genes in AML cells, including the expression of LYL1. Further functional analysis indicated that LYL1 is required for AML cell growth and survival. These findings promote understanding of AML pathophysiology and elucidated an important role of LYL1 in AML progression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico Tipo de estudio: Prognostic_studies Límite: Child / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico Tipo de estudio: Prognostic_studies Límite: Child / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido