Author(s)

Satoki Nakamura, Tomohiro Yagyu, Tomonari Takemura, Lin Tan, Yasuyuki Nagata, Daisuke Yokota, Isao Hirano, Kiyoshi Shibata, Michio Fujie, Shinya Fujisawa, Kazunori Ohnishi

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The Ras/Raf-1/MEK/ERK pathway is constitutively activated in Bcr-Abl transformed cells, and Ras activity enhances the oncogenic ability of Bcr-Abl. On the hand, Raf kinase inhibitor protein (RKIP) inhibits activation of MEK by Raf-1 and its downstream signal transduction, resulting in blocking the MAP kinase pathway. Moreover, Raf-1 has been reported to regulate cell cycle progression. However, the mechanism by which Bcr-Abl promotes the cell cycle progression through Raf-1 is not completely understood. In the present study, we found that the expression of RKIP was suppressed in CML cells, and investigated the interaction between RKIP and Bcr-Abl in CML cells. In aldehyde dehydrogenase (ALDH)^hi/CD34⁺ cells derived from CML patients, the inhibition of Bcr-Abl induced RKIP expression and reduced the phosphorylated-FOXM1 (pFOXM1) status, resulting in inhibited colony formation of Bcr-Abl+ progenitor cells. Moreover, overexpression of RKIP significantly decreased the colony numbers, reduced the pFOXM1 status, and reduced pFOXM-1 target genes such as Skp2, Cdc25B and KIS, and induced the expression of p27^Kip1a and p21^Cip1. Thus, Bcr-Abl represses the expression of RKIP, and continuously activates FOXM1, resulting in the proliferation of CML progenitor cells through the cell cycle modulation.

RKIP; FOXM1; Bcr-Abl; Progenitor cells; Cell cycle

Nakamura, S. , Yagyu, T. , Takemura, T. , Tan, L. , Nagata, Y. , Yokota, D. , Hirano, I. , Shibata, K. , Fujie, M. , Fujisawa, S. and Ohnishi, K. (2011) Bcr-Abl-mediated Raf kinase inhibitor protein suppression promotes chronic myeloid leukemia progenitor cells proliferation. Stem Cell Discovery, 1, 54-66. doi: 10.4236/scd.2011.13006.