Abstract
B-lymphoblastic leukaemic (B-ALL) patients that respond poorly to glucocorticoid therapy are predicted to relapse. An understanding of the biological mechanism underlying this poor responsiveness is therefore crucial for the development of more effective diagnostics and therapies. Forkhead box protein M1 (FOXM1) is a key transcriptional factor that regulates the expression of several genes that promote cell cycle progression, proliferation, DNA repair. Its expression is up-regulated in most cancer cells and is often linked to high proliferation rates and poor responsiveness to the therapy. In this context, we studied the role of FOXM1 in B-lymphoblastic leukaemia (B-ALL) in order to understand if FOXM1 could be a key target for leukaemia therapy. Our results showed that FOXM1 expression is higher in both B-ALL patients and cell lines compared to PBMC or CD19+ cells from healthy donors (Figure 1 A, 1 B). [Display omitted] [Display omitted] Furthermore FOXM1 protein levels were higher in glucocorticoid-resistant cell lines (REH, MHH-CALL2, SEM) when compared to their glucocorticoid-sensitive counterparts (RS4;11, NALM-6), suggesting that FOXM1 may have a role in mediating chemotherapeutic drug sensitivity and resistance in B-ALL. Furthermore, depletion of FOXM1 activity in B-ALL cell lines by either transient knockdown or treatment with a FOXM1 inhibitor, thiostrepton, significantly decreases the cell viability of cells that poorly respond to glucocorticoid treatment (REH). The decrease of cell viability was accompanied by an induction of G2/M arrest of the cell cycle along with a reduction of the S phase. Moreover thiostrepton synergises with common chemotherapeutic agents used in B-ALL therapy increasing their efficiency and overcoming drug resistance.All this data suggest that FOXM1 could be an important therapeutic target for overcoming the resistance to the conventional chemotherapeutic drugs. DisclosuresNo relevant conflicts of interest to declare.
Highlights
Forkhead box protein M1 (FOXM1) is a member of the Forkhead family of transcription factors, previously known as Trident, HFH-11, WIN or INS-1, MPP-2 and FKHL-16 [1]
FOXM1 is an important cell cycle regulator and plays a crucial role in tumorigenesis and its overexpression has been found in many different human cancers
Our aim was to investigate the role of FOXM1 in B-ALL, the most common pediatric leukemia
Summary
FOXM1 is a member of the Forkhead family of transcription factors, previously known as Trident (in mouse), HFH-11 (in human), WIN or INS-1 (in rat), MPP-2 (partial human cDNA) and FKHL-16 [1]. FOXM1 expression increases at the entry of the S-phase of the cell cycle, remains stable during G2/M phase, before being degraded at the mitotic exit [2,3]. FOXM1 controls mitosis through the transcriptional regulation of mitotic regulatory genes, including PLK, Cyclin B1, Aurora A and B kinases [4], and in addition, it plays a major role in maintaining chromosome stability [2]. FOXM1 has an important role in cell cycle progression and cell proliferation. FOXM1 is highly expressed in all embryonic tissues, in proliferating cells of epithelial and mesenchymal origin [5]. Its overexpression has been detected in numerous human cancer cell lines and has been associated with the development and progression of many malignancies [6,7], with high cell proliferation rates, drug resistance [8,9,10] and poor prognosis in many cancer types [11,12,13,14,15]
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