Abstract
Current strategies are not especially successful in the treatment of acute myeloid leukemia (AML). The identification and characterization of oncogenes crucial to the survival and growth of leukemia cells will provide potential targets for the exploitation of novel therapies. Herein, we report that the elevated expression of SH3 domain-binding protein 5 (SH3BP5) significantly correlates with poor outcomes of AML patients. To test whether SH3BP5 contributes to the growth and survival of AML cells, we use the shRNA-encoding lentivirus system to achieve the knockdown of SH3BP5 expression in human AML cell lines U937, THP-1, Kasumi-1, and MV4-11. Functionally, the knockdown of SH3BP5 expression markedly inhibits the cell viability and induced apoptosis of these leukemia cells. Mechanistically, western blot analysis indicates that the knockdown of SH3BP5 expression decreases the phosphorylation of JNK and BAD. Moreover, the JNK agonist anisomycin rescues the growth inhibition phenotype of SH3BP5 deficiency in THP-1 cells. Moreover, the expression of SH3BP5 positively correlates with CD25 and CD123 levels. Finally, our study highlights the crucial role of SH3BP5 in promoting the survival of AML cells, and its suppression may be a potential therapeutic strategy for treating human AML.
Highlights
Despite the rapidly growing armamentarium of effective biologic agents and targeted therapies, acute myeloid leukemia (AML) remains a serious challenge for patients and hematologists
To investigate the expression profile of SH3 domain-binding protein 5 (SH3BP5) in human AML cells, microarray data derived from the Gene Expression Omnibus (GEO) database (GSE6236, GSE1010, and GSE1159) were analyzed
The results suggested that expression of SH3BP5 in AML patients was significantly higher than that in healthy samples (Figure 1A)
Summary
Despite the rapidly growing armamentarium of effective biologic agents and targeted therapies, AML remains a serious challenge for patients and hematologists. A variety of treatment methods such as targeted therapy, immunotherapy, and stem cell transplantation have been established, they all have certain drawbacks and still cannot achieve ideal results. It is imminent to continue to explore more effective methods for treating AML. To identify novel therapeutic targets in human AML, we have established a systematic approach to explore potential genes important for leukemia propagation. We determine new genes that correlate with the outcomes of AML patients using clinical databases. We determine the biological function of the candidate genes using a loss-of-function approach in vitro. We validate the function of target candidate genes in leukemia mouse models in vivo.
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