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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4417-4426.
Prepublished online as a Blood First Edition Paper on August 30, 2007; DOI 10.1182/blood-2007-05-092098.
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NEOPLASIA
The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia
Xavier Leleu1,2,
Xiaoying Jia1,
Judith Runnels3,
Hai T. Ngo1,
Anne-Sophie Moreau1,2,
Mena Farag1,
Joel A. Spencer3,
Costas M. Pitsillides3,
Evdoxia Hatjiharissi1,
Aldo Roccaro1,
Garrett O'Sullivan1,
Douglas W. McMillin1,
Daisy Moreno1,
Tanyel Kiziltepe1,
Ruben Carrasco1,
Steven P. Treon1,
Teru Hideshima1,
Kenneth C. Anderson1,
Charles P. Lin3, and
Irene M. Ghobrial1
1 Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
2 Service des maladies du sang et Laboratoire d'Immunologie, Centre Hospitalier Regional Universitaire (CHRU), Lille, France; and
3 Advanced Microscopy Program, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston
Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma. We demonstrate up-regulated Akt activity in WM, and that Akt down-regulation by Akt knockdown and the inhibitor perifosine leads to significant inhibition of proliferation and induction of apoptosis in WM cells in vitro, but not in normal donor peripheral blood and hematopoietic progenitors. Importantly, down-regulation of Akt induced cytotoxicity of WM cells in the bone marrow microenvironment (BMM) context. Perifosine induced significant reduction in WM tumor growth in vivo in a subcutaneous xenograft model through inhibition of Akt phosphorylation and downstream targets. We also demonstrated that Akt pathway down-regulation inhibited migration and adhesion in vitro and homing of WM tumor cells to the BMM in vivo. Proteomic analysis identified other signaling pathways modulated by perifosine, such as activation of ERK MAPK pathway, which induces survival of tumor cells. Interestingly, MEK inhibitor significantly enhanced perifosine-induced cytotoxicity in WM cells. Using Akt knockdown experiments and specific Akt and PI3K inhibitors, we demonstrated that ERK activation is through a direct effect, rather than feedback activation, of perifosine upstream ERK pathway. These results provide understanding of biological effects of Akt pathway in WM and provide the framework for clinical evaluation of perifosine in WM patients.
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