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Rapamycin restores p14, p15 and p57 expression and inhibits the mTOR/p70S6K pathway in acute lymphoblastic leukemia cells

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Abstract

The aim of the present study was to investigate the effects of rapamycin and its underlying mechanisms on acute lymphoblastic leukemia (ALL) cells. We found that the p14, p15, and p57 genes were not expressed in ALL cell lines (Molt-4 and Nalm-6) and adult ALL patients, whereas mTOR, 4E-BP1, and p70S6K were highly expressed. In Molt-4 and Nalm-6 cells exposed to rapamycin, cell viability decreased and the cell cycle was arrested at the G1/S phase. Rapamycin restored p14, p15, and p57 gene expression through demethylation of the promoters of these genes. As expected, rapamycin also increased p14 and p15 protein expression in both Molt-4 and Nalm-6 cells, as well as p57 protein expression in Nalm-6 cells. Rapamycin additionally decreased mTOR and p70S6K mRNA levels, as well as p70S6K and p-p70S6K protein levels. However, depletion of mTOR by siRNA did not alter the expression and promoter methylation states of p14, p15, and p57. These results indicate that the inhibitory effect of rapamycin may be due mainly to increased p14, p15, and p57 expression via promoter demethylation and decreased mTOR and p70S6K expression in ALL cell lines. These results suggest a potential role for rapamycin in the treatment of adult ALL.

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Acknowledgments

The authors wish to thank Fenglin Cao from the Institute of Hematology and Oncology (Heilongjiang Province) for providing technical assistance. We also thank Dr. Yinchang Mi from the Institute of Hematology and Blood Disease Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College for providing the Molt-4 and Nalm-6 cell lines. This research was supported by the Ph.D. Programs Foundation of the Ministry of Education of China (20132307110022), the Science and Technology project of Heilongjiang Province (GC12C303-4), the Foundation for the Returned Overseas Chinese Scholars of Heilongjiang Province (LCO7C22), the Application Technology Research and Development Project of the Harbin Science and Technology Bureau (2014RFQGJ145), and the Science Foundation of the First Affiliated Hospital at Harbin Medical University (2013B14).

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  1. Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China

    Huibo Li, Xiaolin Kong, Gang Cui, Cuicui Ren, Shengjin Fan, Lili Sun, Yingjie Zhang, Rongyi Cao, Yinghua Li & Jin Zhou

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  1. Huibo Li
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  2. Xiaolin Kong
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  3. Gang Cui
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Correspondence to Yinghua Li.

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Li, H., Kong, X., Cui, G. et al. Rapamycin restores p14, p15 and p57 expression and inhibits the mTOR/p70S6K pathway in acute lymphoblastic leukemia cells. Int J Hematol 102, 558–568 (2015). https://doi.org/10.1007/s12185-015-1858-1

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