NPM1 mediated up - regulation of CXCR4 might drive bortezomib resistance in multiple Myeloma.
Bortezomib (BTZ) containing regimens induces significant antitumor response in multiple myeloma (MM) and are considered as the first-line treatment. However, resistance is still one of the unsolved problems. This study aims to explore the mechanism underlying BTZ resistance in MM.
The gene expression profile (GEP) data of the GEO dataset GSE9782 was analyzed. All cases were divided into BTZ sensitive and resistant arms. Differentially expressed genes (DEGs) and later the hub genes between the two groups were screened. The key hub gene NPM1 was inhibited by shRNA and small molecule inhibitor, proliferation, apoptosis and expression of CXCR4 in myeloma cells were assayed.
NPM1 was a dismal survival prognostic factor in MM, and MM patients with high NPM1 expression achieved significantly lower response rate to BTZ-containing regimens. In vitro, qRT-PCR revealed that NPM1 expression in the BTZ-resistant MM cell line KM3/BTZ (also known as KB) was significantly higher than its parental cell line KM3 cells. Knockdown of NPM1 and treatment with the NPM1 inhibitor NSC348884 both restored the sensitivity of KB cells to BTZ. Further analysis revealed that inhibition of NPM1 down-regulated CXCR4 expression at both transcriptional and translational level.
In conclusion, NPM1 might causes BTZ resistance via up-regulating CXCR4 expression in MM and could be served as both a new prognostic biomarker and a promising therapeutic target.
The gene expression profile (GEP) data of the GEO dataset GSE9782 was analyzed. All cases were divided into BTZ sensitive and resistant arms. Differentially expressed genes (DEGs) and later the hub genes between the two groups were screened. The key hub gene NPM1 was inhibited by shRNA and small molecule inhibitor, proliferation, apoptosis and expression of CXCR4 in myeloma cells were assayed.
NPM1 was a dismal survival prognostic factor in MM, and MM patients with high NPM1 expression achieved significantly lower response rate to BTZ-containing regimens. In vitro, qRT-PCR revealed that NPM1 expression in the BTZ-resistant MM cell line KM3/BTZ (also known as KB) was significantly higher than its parental cell line KM3 cells. Knockdown of NPM1 and treatment with the NPM1 inhibitor NSC348884 both restored the sensitivity of KB cells to BTZ. Further analysis revealed that inhibition of NPM1 down-regulated CXCR4 expression at both transcriptional and translational level.
In conclusion, NPM1 might causes BTZ resistance via up-regulating CXCR4 expression in MM and could be served as both a new prognostic biomarker and a promising therapeutic target.