期刊
CANCER SCIENCE
卷 103, 期 12, 页码 2056-2063出版社
WILEY
DOI: 10.1111/cas.12008
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资金
- National Natural Science Foundation of China [30971296, 81170485, 81200360, 81170488]
- Natural Science Foundation of Jiangsu Province [BK2010584, BK2012484]
- Key Projects of the Health Department of Jiangsu Province [K201108]
- Jiangsu Province's Medical Elite Program [RC2011169]
- University Doctoral Foundation of the Ministry of Education of China [20093234110010]
- Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Project of the National Key Clinical Specialty
The purpose of the present study was to investigate the prognostic significance of murine double minute 4 (MDM4) in chronic lymphocytic leukemia (CLL) and to characterize the role of MDM4 in the p53 pathway. Full-length MDM4 (FL-MDM4), a splicing variant of MDM4 (S-MDM4) and murine double minute 2 (MDM2) mRNA expressions were detected by quantitative PCR in 140 Chinese patients with CLL, and primary CLL cells were treated in vitro with either fludarabine or Nutlin-3 to explore the interaction between p53 status and MDM4 or MDM2 expression. A marked increase of FL-MDM4 and S-MDM4 expressions were observed in the CLL patients with p53 aberrations (deletion and/or mutation) (P = 0.024, P < 0.001). A high level of S-MDM4 mRNA expression was associated with short treatment free survival (TFS) (P = 0.004). FL-MDM4 expression was significantly decreased after fludarabine treatment (P = 0.001) but increased after Nutlin-3 treatment (P = 0.008) of primary CLL cells without p53 aberrations. Both S-MDM4 and MDM2 expressions were significantly increased after fludarabine treatment of CLL cells without p53 aberrations (P = 0.013 and P = 0.030). MDM2 overexpression also occurred in CLL cells with p53 wild type after Nutlin-3 treatment (P = 0.018). FL-MDM4 and S-MDM4 overexpression are indicators of p53 aberrations in CLL patients, suggesting that those patients have a poor prognosis. FL-MDM4 inhibitory effects on p53 can be removed by MDM2-p53 and saved by Nutlin-3. (Cancer Sci 2012; 103: 2056-2063)
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