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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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Submitted May 25, 2007
Accepted August 20, 2007
The Akt pathway regulates survival and homing in Waldenstrom Macroglobulinemia
Xavier Leleu, Xiaoying Jia, Judith Runnels, Hai T Ngo, Anne-Sophie Moreau, Mena Farag, Joel A Spencer, Costas M Pitsillides, Evdoxia Hatjiharissi, Aldo Roccaro, Garrett O'Sullivan, Douglas W. McMillin, Daisy Moreno, Tanyel Kiziltepe, Ruben Carrasco, Steven P Treon, Teru Hideshima, Kenneth C Anderson, Charles P Lin, and Irene M Ghobrial*
Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States
Advanced Microscopy Program, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, United States
Service des maladies du sang et Laboratoire d'Immunologie, CHRU, Lille, France
* Corresponding author; email: irene_ghobrial{at}dfci.harvard.edu.
Waldenstrom Macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma. We demonstrate upregulated Akt activity in WM, and that Akt downregulation 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, downregulation 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 downregulation 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, that 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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