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Blood, 1 April 2007, Vol. 109, No. 7, pp. 3031-3041.
Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-07-032714.
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Submitted July 5, 2006
Accepted November 12, 2006
Identification of mcl-1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by mcl-1 antisense oligonucleotides
and synergism with PKC412
Karl J. Aichberger, Matthias Mayerhofer, Karoline V. Gleixner, Maria-Theresa Krauth, Alexander Gruze, Winfried F. Pickl, Volker Wacheck, Edgar Selzer, Leonhard Mullauer, Hermine Agis, Christian Sillaber, and Peter Valent*
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria
Institute of Immunology, Medical University of Vienna, Vienna, Austria
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Department of Radiation Therapy, Medical University of Vienna, Vienna, Austria
Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria
* Corresponding author; email: peter.valent{at}meduniwien.ac.at.
Mcl-1 is a Bcl-2 family-member that has been described to act antiapoptotic in various myeloid neoplasms and therefore has been proposed as a potential new therapeutic target. Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MC) and their progenitors. In the present study, we examined the expression and functional role of Mcl-1 in neoplastic MC and asked whether Mcl-1 could serve as a target in SM. As assessed by RT-PCR and immunohistochemistry, primary neoplastic MC were found to express mcl-1 mRNA and the Mcl-1 protein in all SM patients examined. Moreover, Mcl-1 was detectable in both subclones of the MC line HMC-1, namely HMC-1.1 lacking the SM-related KIT mutation D816V, and in HMC-1.2 cells carrying KIT D816V. Exposure of HMC-1.1 cells or HMC-1.2 cells to mcl-1-specific antisense oligonucleotides (ASO) or mcl-1-specific siRNA resulted in reduced survival and increased apoptosis compared to untreated cells. Moreover, mcl-1 ASO were found to cooperate with various tyrosine kinase inhibitors in producing growth inhibition in neoplastic MC, with synergistic effects being observed with PKC412, AMN107, and imatinib in HMC-1.1 cells, and with PKC412 in HMC-1.2 cells. Together, these data show that Mcl-1 is a novel survival factor and attractive target in neoplastic MC.
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