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

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.

MicroRNA‐145‐5p suppresses cell proliferation, migration, and invasion in upper tract urothelial carcinoma by targeting 5‐aminoimidazole‐4‐carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase

“…DPYSL2, also known as CRMP2, is a collapsin response mediator protein, whose physiological function is to primarily regulate axonal growth. Recent studies have revealed that DPYSL2 is more highly expressed in human colorectal cancer, non‐small cell lung cancer, bladder cancer, and acute myeloid leukemia (AML) than in normal tissues and may serve as a prognostic biomarker 34–37 . In vitro and in vivo experiments on DPYSL2 showed that it promotes the proliferation, migration, and invasive abilities of bladder cancer cells by regulating aerobic glycolysis and EMT through pyruvate kinase M2 36 .…”

“…The interaction between DPYSL2 and Janus kinase 1 was shown to promote the migration of breast cancer cells by regulating the signal transducer and activator of transcription 3 (STAT3)/vimentin pathway 38 . Furthermore, the inhibition of DPYSL2 suppresses AML cell growth and promotes apoptosis via the JAK2/STAT3/5 and PI3K P85/AKT/GSK3β pathways 37 . Thus, DPYSL2 may play an oncogenic role in tumors, and future studies should explore whether miR‐145‐5p can directly regulate the expression of DPYSL2 and affect the function of UTUC.…”

“…Recent studies have revealed that DPYSL2 is more highly expressed in human colorectal cancer, non-small cell lung cancer, bladder cancer, and acute myeloid leukemia (AML) than in normal tissues and may serve as a prognostic biomarker. [34][35][36][37] In vitro and in vivo experiments on DPYSL2 showed that it promotes the proliferation, migration, and invasive abilities of bladder cancer cells by regulating aerobic glycolysis and EMT through pyruvate kinase M2. 36 The interaction between DPYSL2 and Janus kinase 1 was shown to promote the migration of breast cancer cells by regulating the signal transducer and activator of transcription 3 (STAT3)/vimentin pathway.…”

“…38 Furthermore, the inhibition of DPYSL2 suppresses AML cell growth and promotes apoptosis via the JAK2/STAT3/5 and PI3K P85/AKT/GSK3β pathways. 37 Thus, DPYSL2 may play an oncogenic role in tumors, and future studies should explore whether miR-145-5p can directly regulate the expression of DPYSL2 and affect the function of UTUC. The other nine proteins did not show any binding relationship with miR-145-5p, but miR-145-5p may indirectly affect the expression of these proteins by regulating other molecules.…”

Prognostic Significance of Dual-Specificity Phosphatase 23 Expression in Acute Myeloid Leukemia

“…Therefore, it is necessary to discover novel biomarkers to better understand the molecular basis of AML. 3 , 4 …”