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 p27Kip1a and p21Cip1. 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.
Highlights
Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy that is characterized by the Philadelphia chromosome [1,2], a shortened chromosome 22 that is a by-product of a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22 t (9; 22) (q34; q11), resulting in a chimeric Bcr-Abl oncoprotein with highly deregulated, constitutive tyrosine kinase activity [3,4]
We found that the expression of Raf kinase inhibitor protein (RKIP) mRNA increased in the three CML cell lines treated with Abl kinase inhibitors (STI571, AMN107, or BMS35482 5) for 24 h as compared to untreated cells
These results demonstrate that the inhibition for Bcr-Abl expression induced the RKIP expression and reduced the phosphorylation levels of FOXM1, and the overexpression of RKIP inhibited the colony formation of ALDHhi/CD34+ cells from CML specimens through the reduction of the pFOXM1 status
Summary
Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy that is characterized by the Philadelphia chromosome [1,2], a shortened chromosome 22 that is a by-product of a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22 t (9; 22) (q34; q11), resulting in a chimeric Bcr-Abl oncoprotein with highly deregulated, constitutive tyrosine kinase activity [3,4]. Bcr-Abl activates a variety of signaling pathways, including the Ras/Raf1/MEK/ERK [6], PI3K/Akt [7], JAK/STAT [8], and NFκB [9] signaling pathways. These signaling pathways play important role in Bcr-Abl-mediated leukemogenesis. The Ras pathway regulates multiple biological aspects including mitogenesis and differentiation [10,11], and is constitutively activated in Bcr-Abl transformed cells. Inhibition of Ras activity represses the oncogenic ability of Bcr-Abl [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
