Abstract
Glucocorticoids are widely used to treat B acute lymphoblastic leukemia (B-ALL); however, the molecular mechanism underlying glucocorticoid response and resistance is unclear. In this study, the role and regulation of FOXO3a in mediating the dexamethasone response in B-ALL were investigated. The results show that FOXO3a mediates the cytotoxic function of dexamethasone. In response to dexamethasone, it was found that FOXO3a translocates into the nucleus, where it induces the expression of downstream targets, including p27Kip1 and Bim, important for proliferative arrest and cell death in the sensitive RS4;11 and SUP-B15 B-ALL cells. FOXO3a activation by dexamethasone is mediated partially through the suppression of the PI3K/Akt signaling cascade. Furthermore, two posttranslational modifications were uncovered, phosphorylation on Ser-7 and acetylation on Lys-242/5, that associated with FOXO3a activation by dexamethasone. Immunoblot analysis showed that the phosphorylation on Ser-7 of FOXO3a is associated with p38/JNK activation, whereas the acetylation on Lys-242/5 is correlated with the downregulation of SIRT1/2/6 and the induction of the acetyltransferase CBP/p300. Collectively, these results indicate that FOXO3a is essential for dexamethasone response in B-ALL cells, and its nuclear translocation and activation is associated with its phosphorylation on Ser-7 and acetylation on Lys-242/245. These posttranslational events can be exploited as biomarkers for B-ALL diagnosis and as drug targets for B-ALL treatment, particularly for overcoming the glucocorticoid resistance. FOXO3a and its posttranslational regulation are essential for dexamethasone response, and targeting FOXO3a and sirtuins may enhance the dexamethasone-induced cytotoxicity in B-ALL cells.
Highlights
B acute lymphoblastic leukemia (B-ALL) is one of the most common clonal malignant diseases in children, and it stems from unchecked proliferation of lymphoid progenitor cells
Unlike FOXO3a, the expression of the other FOXO family members, FOXO1 and FOXO4, was expressed at low levels in the sensitive cells before and after dexamethasone, suggesting that FOXO1 and FOXO4 are unlikely to have a crucial part to play in dexamethasone response (Fig. 1A)
These results suggest that after treatment, FOXO3a becomes hypophosphorylated at Akt-dependent sites and activated in the sensitive B-ALL cells
Summary
B acute lymphoblastic leukemia (B-ALL) is one of the most common clonal malignant diseases in children, and it stems from unchecked proliferation of lymphoid progenitor cells. Glucocorticoids are the most effective and commonly used agents for treatment of B-ALL; their efficacy is often hampered by the development of resistance [1]. Glucocorticoid sensitivity at diagnosis has a major bearing on the eventual clinical outcome for patients with childhood In consequence, uncovering the mechanisms that underlie dexamethasone responsiveness will help identify reliable biomarkers for early diagnosis and for predicting disease relapse and aid the design of targeted therapies to overcome glucocorticoid resistance in B-ALL. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
