| Literature DB >> 25925206 |
L Mourgues1,2,3, V Imbert1,2,3, M Nebout1,2,3, P Colosetti1,3,4, Z Neffati1,2,3, P Lagadec1,2,3, E Verhoeyen1,4,5, C Peng6, E Duprez7, L Legros3,8,9, N Rochet3,9, V Maguer-Satta10, F-E Nicolini11, D Mary1,2,3, J-F Peyron1,2,3.
Abstract
The BMI1 polycomb protein regulates self-renewal, proliferation and survival of cancer-initiating cells essentially through epigenetic repression of the CDKN2A tumor suppressor locus. We demonstrate here for the first time that BMI1 also prevents autophagy in chronic myeloid leukemia (CML) cell lines, to support their proliferation and clonogenic activity. Using chromatin immunoprecipitation, we identified CCNG2/cyclin G2 (CCNG2) as a direct BMI1 target. BMI1 downregulation in CD34+ CML cells by PTC-209 pharmacological treatment or shBMI1 transduction triggered CCNG2 expression and decreased clonogenic activity. Also, ectopic expression of CCNG2 in CD34+ CML cells strongly decreased their clonogenicity. CCNG2 was shown to act by disrupting the phosphatase 2A complex, which activates a PKCζ-AMPK-JNK-ERK pathway that engages autophagy. We observed that BMI1 and CCNG2 levels evolved inversely during the progression of CML towards an acute deadly phase, and therefore hypothesized that BMI1 could support acute transformation of CML through the silencing of a CCNG2-mediated tumor-suppressive autophagy response.Entities:
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Year: 2015 PMID： 25925206 DOI： 10.1038/leu.2015.112
Source DB: PubMed Journal: Leukemia ISSN： 0887-6924 Impact factor: 11.528