Bcr-Abl-mediated Raf kinase inhibitor protein suppression promotes chronic myeloid leukemia progenitor cells proliferation

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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DOI: 10.4236/scd.2011.13006                

Abstract

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.

Keywords

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

Conflicts of Interest

The authors declare no conflicts of interest.

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