Submitted November 6, 2007
Accepted June 11, 2008
Combined functional and molecular analysis of tumor cell signaling defines two distinct myeloma subgroups: Akt-dependent and Akt-independent multiple myeloma
Angela Zollinger, Thorsten Stuhmer*, Manik Chatterjee, Stefan Gattenlohner, Eugenia Haralambieva, Hans-Konrad Muller-Hermelink, Mindaugas Andrulis, Axel Greiner, Carmen Wesemeier, Jorg C Rath, Hermann Einsele, and Ralf C Bargou
Division of Hematology, Department of Internal Medicine II, University Hospital of Wurzburg, Wurzburg, Germany
Institute of Pathology, University Hospital of Wurzburg, Wurzburg, Germany
Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
Institute of Pathology and Cytology, Deggendorf, Germany
* Corresponding author; email: stuehmer_t{at}medizin.uni-wuerzburg.de.
Although the phosphatidylinositide 3-kinase (PI3K)/Akt pathway has been reported to contribute to the malignant growth of multiple myeloma (MM) the true relevance of Akt kinase for this disease is still unclear. In particular, functional analyses in primary tumor cells and genetic target validation experiments are missing. Here, we employed combined functional and molecular analyses to determine the importance of Akt activity in a large panel of primary MM samples and in MM cell lines. Akt downregulation with isoform-specific siRNA constructs or with an Akt1/2-specific pharmacologic inhibitor strongly induced apoptosis in about half of the primary MM samples analyzed. Sensitivity to Akt inhibition strongly correlated with the activation status of Akt as determined by immunohistochemistry, phospho-Akt-specific flow cytometry, and Western analysis. Additional blockade of the MAPK and the IL-6R/STAT3 pathways was often not sufficient to decrease the viability of MM cells resilient to Akt inhibition. Taken together, these experiments led to the identification of two myeloma subgroups: Akt-dependent and Akt-independent MM.
