Aichberger KJ, Gleixner KV, Mirkina I, Cerny-Reiterer S, Peter B, Ferenc V, Kneidinger M, Baumgartner C, Mayerhofer M, Gruze A, Pickl WF, Sillaber C, Valent P
Identification of pro-apoptotic Bim as a tumor suppressorin neoplastic mast cells: role of KIT D816V and effects of various targeted drugs. [JOURNAL ARTICLE]
Blood 2009 Oct 22.
Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MC) and their progenitors. In most cases, neoplastic cells display the D816V-mutated variant of KIT. KIT D816V exhibits constitutive tyrosine kinase (TK) activity and has been implicated in increased survival and growth of neoplastic MC. Recent data suggest that the pro-apoptotic BH3-only death regulator Bim plays a role as a tumor-suppressor in various myeloid neoplasms. We found that KIT D816V suppresses expression of Bim in Ba/F3 cells. The KIT D816-induced downregulation of Bim was rescued by the KIT-targeting drug PKC412/midostaurin. Both PKC412 and the proteasome-inhibitor bortezomib were found to decrease growth and to promote expression of Bim in the MC leukemia cell lines HMC-1.1 (D816V-negative) and HMC-1.2 (D816V-positive). Both drugs were also found to counteract growth of primary neoplastic MC. Furthermore, midostaurin was found to cooperate with bortezomib and with the BH3-mimetic obatoclax in producing growth-inhibition in both HMC-1 subclones. Finally, a Bim-specific siRNA was found to rescue HMC-1 cells from PKC412-induced cell death. Together, our data show that KIT D816V suppresses expression of pro-apoptotic Bim in neoplastic MC. Targeting of Bcl-2-family members by drugs promoting Bim-(re)expression or by BH3-mimetics like obatoclax, may be an attractive therapeutic approach in SM.
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