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 Blood, 15 October 2008, Vol. 112, No. 8, pp. 3403-3411.
Prepublished online as a Blood First Edition Paper on July 17, 2008; DOI 10.1182/blood-2007-11-119362.

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NEOPLASIA

Combined functional and molecular analysis of tumor cell signaling defines 2 distinct myeloma subgroups: Akt-dependent and Akt-independent multiple myeloma

Angela Zöllinger1, Thorsten Stühmer1, Manik Chatterjee1, Stefan Gattenlöhner2, Eugenia Haralambieva2, Hans-Konrad Müller-Hermelink2, Mindaugas Andrulis3, Axel Greiner4, Carmen Wesemeier1, Jörg C. Rath1, Hermann Einsele1, and Ralf C. Bargou1

1 Department of Internal Medicine II, Division of Hematology and 2 Institute of Pathology, University Hospital of Würzburg, Würzburg; 3 Institute of Pathology, University Hospital of Heidelberg, Heidelberg; and 4 Institute of Pathology and Cytology, Deggendorf, Germany

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 kinases for this disease is still unclear. In particular, functional analyses in primary tumor cells and genetic target validation experiments are missing. Here, we used 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 down-regulation with isoform-specific siRNA constructs or with an Akt1/2-specific pharmacologic inhibitor strongly induced apoptosis in approximately 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 2 myeloma subgroups: Akt-dependent and Akt-independent MM.


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Related Article in Blood Online:

Need akt? Some myelomas do
P.Leif Bergsagel
Blood 2008 112: 3004-3005. [Full Text] [PDF]





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