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 Blood, 15 September 2008, Vol. 112, No. 6, pp. 2305-2317.
Prepublished online as a Blood First Edition Paper on July 11, 2008; DOI 10.1182/blood-2007-09-111856.

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HEMATOPOIESIS AND STEM CELLS

Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation

Meaghan Wall1,2, Gretchen Poortinga1, Katherine M. Hannan1, Richard B. Pearson1,3,4, Ross D. Hannan1,3,4, and Grant A. McArthur1,2,5

1 Division of Research, Peter MacCallum Cancer Centre, East Melbourne; 2 Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy; 3 Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville; 4 Department of Biochemistry and Molecular Biology, Monash University, Clayton; and 5 Division of Haematology/Medical Oncology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Australia

c-MYC inhibits differentiation and regulates the process by which cells acquire biomass, cell growth. Down-regulation of c-MYC, reduced cell growth, and decreased activity of the PI3K/AKT/mTORC1 signal transduction pathway are features of the terminal differentiation of committed myeloid precursors to polymorphonuclear neutrophils. Since mTORC1 regulates growth, we hypothesized that pharmacological inhibition of mTORC1 by rapamycin may reverse the phenotypic effects of c-MYC. Here we show that granulocytes blocked in their ability to differentiate by enforced expression of c-MYC can be induced to differentiate by reducing exogenous c-MYC expression through rapamycin treatment. Rapamycin also reduced expression of endogenous c-MYC and resulted in enhanced retinoid-induced differentiation. Total cellular c-Myc mRNA and c-MYC protein stability were unchanged by rapamycin, however the amount of c-Myc mRNA associated with polysomes was reduced. Therefore rapamycin limited expression of c-MYC by inhibiting c-Myc mRNA translation. These findings suggest that mTORC1 could be targeted to promote terminal differentiation in myeloid malignancies characterized by dysregulated expression of c-MYC.


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