Dihydropyrimidinase‐like 2 can serve as a novel therapeutic target and prognostic biomarker in acute myeloid leukemia

Fenglin Li; Qing Ling; Jiaying Lian; Ying Chen; Chao Hu; Min Yang; Xiang Zhang; Chenying Li; Shihui Mao; Wenle Ye; Xia Li; Xiangjie Lin; Wenwen Wei; Xin Huang; Jiajia Pan; Yu Qian; Jinghan Wang; Ying Lu; Jie Jin

doi:10.1002/cam4.5531

Cancer Medicine (Apr 2023)

Dihydropyrimidinase‐like 2 can serve as a novel therapeutic target and prognostic biomarker in acute myeloid leukemia

Fenglin Li,
Qing Ling,
Jiaying Lian,
Ying Chen,
Chao Hu,
Min Yang,
Xiang Zhang,
Chenying Li,
Shihui Mao,
Wenle Ye,
Xia Li,
Xiangjie Lin,
Wenwen Wei,
Xin Huang,
Jiajia Pan,
Yu Qian,
Jinghan Wang,
Ying Lu,
Jie Jin

Affiliations

Fenglin Li: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Qing Ling: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Jiaying Lian: Department of Hematology The affiliated people's hospital of Ningbo University Ningbo China
Ying Chen: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Chao Hu: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Min Yang: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Xiang Zhang: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Chenying Li: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Shihui Mao: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Wenle Ye: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Xia Li: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Xiangjie Lin: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Wenwen Wei: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Xin Huang: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Jiajia Pan: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Yu Qian: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Jinghan Wang: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China
Ying Lu: Department of Hematology The affiliated people's hospital of Ningbo University Ningbo China
Jie Jin: Department of Hematology, the First Affiliated Hospital Zhejiang University, College of Medicine Hangzhou Zhejiang People's Republic of China

DOI: https://doi.org/10.1002/cam4.5531
Journal volume & issue: Vol. 12, no. 7
pp. 8319 – 8330

Abstract

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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.

Published in Cancer Medicine

ISSN: 2045-7634 (Online)
Publisher: Wiley
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://onlinelibrary.wiley.com/journal/20457634

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