Journal Article

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

Satoki Nakamura, Isao Hirano, Keiji Okinaka, Tomonari Takemura, Daisuke Yokota, Takaaki Ono, Kazuyuki Shigeno, Kiyoshi Shibata, Shinya Fujisawa and Kazunori Ohnishi

in Carcinogenesis

Volume 31, issue 11, pages 2012-2021
Published in print November 2010 | ISSN: 0143-3334
Published online September 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq185
The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia

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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 higher than in normal high aldehyde dehydrogenase activity (ALDHhi) cells. Reduction of FOXM1 expression in AML cells inhibited cell proliferation compared with control cells, through induction of G2/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 p21Cip1 and p27Kip1. FOXM1 messenger RNA (mRNA) was overexpressed in all 127 AML clinical specimens tested (n = 21, 56, 32 and 18 for M1, M2, M4 and M5 subtypes, respectively). Compared with normal ALDHhi cells, FOXM1 gene expression was 1.65- to 2.26-fold higher in AML cells. Moreover, the FOXM1 protein was more strongly expressed in AML-derived ALDHhi cells compared with normal ALDHhi cells. In addition, depletion of FOXM1 reduced colony formation of AML-derived ALDHhi 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.

Journal Article.  7101 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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