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A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein beta and NF-kappaB activity in Hodgkin and anaplastic large cell lymphomas

Official URL:https://doi.org/10.1182/blood-2004-11-4513
PubMed:View item in PubMed
Creators Name:Jundt, F. and Raetzel, N. and Mueller, C. and Calkhoven, C.F. and Kley, K. and Mathas, S. and Lietz, A. and Leutz, A. and Doerken, B.
Journal Title:Blood
Journal Abbreviation:Blood
Volume:106
Page Range:1801-1807
Date:1 January 2005
Keywords:CCAAT-Enhancer-Binding Protein-beta, Cell Cycle, Cell Proliferation, Down-Regulation, Heterologous Transplantation, Hodgkin Disease, Large B-Cell and Diffuse Lymphoma, NF-kappa B, Sirolimus, Tumor Cell Line, Animals, Mice
Abstract:The immunosuppressive macrolide rapamycin and its derivative everolimus (SDZ RAD, RAD) inhibit the mammalian target of rapamycin (mTOR) signaling pathway. In this study, we provide evidence that RAD has profound antiproliferative activity in vitro and in NOD/SCID mice in vivo against Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) cells. Moreover, we identified 2 molecular mechanisms that showed how RAD exerts antiproliferative effects in HL and ALCL cells. RAD down-regulated the truncated isoform of the transcription factor CCAAT enhancer binding protein β (C/EBPβ), which is known to disrupt terminal differentiation and induce a transformed phenotype. Furthermore, RAD inhibited constitutive nuclear factor κB (NF-κB) activity, which is a critical survival factor of HL cells. Pharmacologic inhibition of the mTOR pathway by RAD therefore interferes with essential proliferation and survival pathways in HL and ALCL cells and might serve as a novel treatment option.
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Item Type:Article

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