Exploring the Involvement of FoxM1 in CML Cells from DNA Damage Response-Regulatory Prospective

Abstract Background FoxM1 is widely accepted as an oncogenesis factor, for it is one of the most frequently upregulated genes in a broad spectrum of human malignancies. Herein, we presented the status of FoxM1 in CML samples and cell lines. Methods We compared FoxM1 abundance and phosphorylation using PB-MNC samples from CML patients and healthy donors. DNA damage response (DDR) was investigated in the presence of oncogene or chemical. Through enforced expression of FoxM1 or lentivirus mediated silencing, we explored the participation of FoxM1 in DDR regulation. Results Overexpression of FoxM1 was only observed in 3 samples from patients of advanced stage. However, hyper-phosphorylation of FoxM1 was evidently detected in the CML cohort. Furtherly, the DNA damage response that in accompany with the formation of Bcr/Abl was responsible for the rise in FoxM1 phosphorylation. Bcr/Abl provoked a modest extent of DNA damage, which, in turn, roused the repair system, mirrored by phosphorylation of the ATM/ATR-CHK1/2 axis. FoxM1 was a downstream target of CHK1 which directly associated with FoxM1 in the presence of DNA damage. Activation of FoxM1 served as a DDR regulator by inducing the expression of Rad51 and Brca1, genes that participated in DNA repair. Depletion of FoxM1 impaired DNA repair, leading to cell cycle arrest in G2/M phase and the onset of apoptosis in a P53-dependent fashion. Finally, our data demonstrated that phosphorylation of FoxM1 did not rely on Bcr/Abl kinase activity. Suppression of FoxM1 showed lethal potential to primary CML cells, and most importantly, the lethality was not affected by the TKIs insensitiveness. Conclusions Abnormality in FoxM1 activity in CML cells enlightened us that constantly present DNA damage rendered leukemia cells more reliant upon the DNA damage repair system. Targeting FoxM1 could be exploit as an alternative strategy to overcome TKIs resistance.