Dihydropyrimidinase‐like 2 can serve as a novel therapeutic target and prognostic biomarker in acute myeloid leukemia. (9th January 2023)

• Record Type: Journal Article
• Authors: Li, Fenglin; Ling, Qing; Lian, Jiaying; Chen, Ying; Hu, Chao; Yang, Min; Zhang, Xiang; Li, Chenying; Mao, Shihui; Ye, Wenle; Li, Xia; Lin, Xiangjie; Wei, Wenwen; Huang, Xin; Pan, Jiajia; Qian, Yu; Wang, Jinghan; Lu, Ying; Jin, Jie
• Is Part Of: Cancer medicine. Volume 12:Number 7(2023)
• Page Start: 8319
• Page End: 8330
• Publication Date: 2023-01-09
• Subjects: AML -- biomarker -- DPYSL2 -- HHT -- PI3K/Akt -- prognostic; 616.994005
• DOI: 10.1002/cam4.5531
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Background: Identifying therapeutic targets and prognostic biomarkers significantly contributes to individualized treatment of acute myeloid leukemia (AML). Dihydropyrimidinase‐like 2 (DPYSL2) expression was decreased in homoharringtonine (HHT)‐resistant AML cells, which were established by our group. DPYSL2 plays an important role in axon growth and has oncogene effect in glioblastoma. However, little research has been conducted to investigate the function of DPYSL2 in AML pathogenesis. Methods: Auto‐docking was used to reveal the targeting relationship between HHT and DPYSL2. Overall survival (OS), event‐free survival (EFS), and relapse‐free survival (RFS) were used to evaluate the prognostic impact of DPYSL2 for AML. ShRNA was used to knockdown the expression of SPATS2L. Apoptosis was assessed by flow cytometry. In vivo growth and survival were assessed using a xenotransplantation mice model. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SPATS2L in AML and were confirmed by Western blot. Results: We found DPYSL2 was the target of HHT. Next, we found AML cell lines and patients had higher DPYSL2 expression levels than the normal samples. Further multivariate analysis demonstrated that high DPYSL2 expression was an independent poor prognostic factor for OS, EFS, and RFS in AML. Inhibition of DPYSL2 expression suppressed cell growth, induced apoptosis in AML cell lines, and prolonged the survival of AML xenograft NCG mice. Through RNA‐seq analysis from TCGA and our data, the JAK2/STAT3/STAT5‐PI3K P85/AKT/GSK3b axis was thought to be the critical pathway in regulating DPYSL2 in AML development. Conclusions: We first time confirmed that DPYSL2 was a target of HHT and played an oncogene role in AML by regulating JAK/STAT signaling pathway. Therefore, DPYSL2 could serve as a novel prognostic marker and therapeutic target for AML treatment. Abstract : DPYSL2 plays an oncogene role in AML and high DPYSL2 expression is an independent prognostic factor for AML patients. Homoharringtonine (HHT) targets DPYSL2 and inhibits the expression of DPYSL2 in AML cells, further reduces the expression of JAK2, STAT3, STAT5, PI3K P85, AKT, GSK3b in JAK/STAT, PI3K/AKT/GSK3b signaling pathways, thus promoting the apoptosis of AML cells.