title: FOXM1 is overexpressed in B-acute lymphoblastic leukemia (B-ALL) and its inhibition sensitizes B-ALL cells to chemotherapeutic drugs.
abstract: The Forkhead box protein M1 (FOXM1) is a transcription factor that plays a central role in the regulation of cell cycle, proliferation, DNA repair, and apoptosis. FOXM1 is overexpressed in many human tumors and its upregulation has been linked to high proliferation rates and poor prognosis. We therefore studied the role of FOXM1 in B-lymphoblastic leukemia (B-ALL) in order to understand whether FOXM1 could be a key target for leukemia therapy. RT-PCR and western blot analysis were carried out in a small cohort of pediatric B-ALL patients to evaluate FOXM1 levels. To assess its biological relevance, its expression was down-modulated by transient RNA interference in B-ALL cell lines (REH and NALM-6). Our results show that FOXM1 expression is higher in both B-ALL patients and cell lines when compared to PBMC or normal B-cells (CD19+) from healthy donors. Furthermore, blocking FOXM1 activity in two B-ALL cell lines, by either knockdown or treatment with the FOXM1 inhibitor thiostrepton, causes significant decrease in their cell proliferation. This decrease in cell proliferation was coupled with both an induction of the G2/M cell cycle arrest and with a reduction in the S phase population. Finally, we noted how thiostrepton synergises with chemotherapeutic agents commonly used in B-ALL therapy, thus increasing their efficiency. Therefore our results suggest that FOXM1 is highly expressed in both patients and B-ALL cell lines, and that targeting FOXM1 could be an attractive strategy for leukemia therapy and for overcoming drug resistance.
authors: Department of Woman's and Child's Health, Oncohematology Laboratory, University of Padova, Padova, Italy.
authors: Francesca
authors: F
authors: Consolaro
authors: Department of Woman's and Child's Health, Oncohematology Laboratory, University of Padova, Padova, Italy.
authors: Giuseppe
authors: G
authors: Basso
authors: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors: Sadaf
authors: S
authors: Ghaem-Magami
authors: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors: Eric W-F
authors: EW
authors: Lam
authors: Department of Woman's and Child's Health, Oncohematology Laboratory, University of Padova, Padova, Italy.
authors: Giampietro
authors: G
authors: Viola
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D007223:Infant; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering