The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia

S. Nakamura, I. Hirano, K. Okinaka, T. Takemura, D. Yokota, T. Ono, K. Shigeno, K. Shibata, S. Fujisawa, K. Ohnishi
2010 Carcinogenesis  
FOXM1 is an important cell cycle regulator and regulates cell proliferation. In addition, FOXM1 has been reported to contribute to oncogenesis in various cancers. However, it is not clearly understood how FOXM1 contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of FOXM1 in AML cells. The FOXM1 messenger RNA (mRNA) expressed in AML cell lines was predominantly the FOXM1B isoform, and its levels were significantly
more » ... er than in normal high aldehyde dehydrogenase activity (ALDH hi ) cells. Reduction of FOXM1 expression in AML cells inhibited cell proliferation compared with control cells, through induction of G 2 /M cell cycle arrest, a decrease in the protein expression of Aurora kinase B, Survivin, Cyclin B1, S-phase kinase-associated protein 2 and Cdc25B and an increase in the protein expression of p21 Cip1 and p27 Kip1 . FOXM1 messenger RNA (mRNA) was overexpressed in all 127 AML clinical specimens tested (n 5 21, 56, 32 and 18 for M1, M2, M4 and M5 subtypes, respectively). Compared with normal ALDH hi cells, FOXM1 gene expression was 1.65-to 2.26-fold higher in AML cells. Moreover, the FOXM1 protein was more strongly expressed in AMLderived ALDH hi cells compared with normal ALDH hi cells. In addition, depletion of FOXM1 reduced colony formation of AML-derived ALDH hi cells due to inhibition of Cdc25B and Cyclin B1 expression. In summary, we found that FOXM1B mRNA is predominantly expressed in AML cells and that aberrant expression of FOXM1 induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of FOXM1 expression represents an attractive target for AML therapy. Abbreviations: ALDH hi , high aldehyde dehydrogenase activity; AML, acute myeloid leukemia; FITC, fluorescein isothiocyanate; KIS, kinase interacting stathmin; MNC, mononuclear cells; mRNA, messenger RNA; PI, propidium iodide; RT-PCR, reverse transcription-polymerase chain reaction; siRNA, small interfering RNA; skp2, S-phase kinase-associated protein 2. y These authors contributed equally.
doi:10.1093/carcin/bgq185 pmid:20823107 fatcat:54zfexprhbe5hn6zis6ymgphyu