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 Blood, 15 July 2007, Vol. 110, No. 2, pp. 661-669.
Prepublished online as a Blood First Edition Paper on April 9, 2007; DOI 10.1182/blood-2006-10-054411.

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NEOPLASIA

Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells

Rudin Kondo1, Karoline V. Gleixner1, Matthias Mayerhofer1,2, Anja Vales1, Alexander Gruze3, Puchit Samorapoompichit4, Khaled Greish5, Maria-Theresa Krauth1, Karl J. Aichberger1, Winfried F. Pickl3, Harald Esterbauer2, Christian Sillaber1, Hiroshi Maeda5, and Peter Valent1

1 Department of Internal Medicine I, Division of Hematology & Hemostaseology 2 Clinical Institute of Medical & Chemical Laboratory Diagnostics 3 Institute of Immunology, and 4 Center of Anatomy & Cell Biology, Medical University of Vienna, Austria; 5 Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Japan

Systemic mastocytosis (SM) is a myeloid neoplasm characterized by increased survival and accumulation of neoplastic mast cells (MCs). In most patients, the D816V-mutated variant of KIT is detectable. We report here that heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a novel KIT-inducible survival factor in neoplastic MCs. As assessed by reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry, and Western blotting, the KIT D816V+ MC line HMC-1.2 as well as highly enriched primary neoplastic MCs were found to express Hsp32 mRNA and the Hsp32 protein. Moreover, KIT D816V and stem cell factor (SCF)–activated wild-type KIT were found to induce Hsp32 promoter activity, expression of Hsp32 mRNA, and expression of the Hsp32 protein in Ba/F3 cells. Correspondingly, the KIT D816V-targeting drug PKC412 decreased the expression of Hsp32 as well as proliferation/survival in neoplastic MCs. The inhibitory effects of PKC412 on the survival of HMC-1.2 cells were counteracted by the HO-1 inductor hemin or lentiviral-transduced HO-1. Moreover, 2 Hsp32-targeting drugs, pegylated zinc protoporphyrin (PEG-ZnPP) and styrene maleic acid copolymer micelle-encapsulated ZnPP (SMA-ZnPP), were found to inhibit proliferation and to induce apoptosis in neoplastic MCs. Furthermore, both drugs were found to cooperate with PKC412 in producing growth inhibition. Together, these data show that Hsp32 is an important survival factor and interesting new therapeutic target in neoplastic MCs.


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Related Article in Blood Online:

Hsp32: MASTer of KIT?
Michel A. Arock
Blood 2007 110: 471. [Full Text] [PDF]



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M. Mayerhofer, K. V. Gleixner, J. Mayerhofer, G. Hoermann, E. Jaeger, K. J. Aichberger, R. G. Ott, K. Greish, H. Nakamura, S. Derdak, et al.
Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib
Blood, February 15, 2008; 111(4): 2200 - 2210.
[Abstract] [Full Text] [PDF]


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