期刊
LEUKEMIA
卷 25, 期 11, 页码 1728-1738出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2011.154
关键词
core binding factor; acute myeloid leukemia; gene expression profiling; apoptosis; BCL2; inhibitor of apoptosis proteins
资金
- Deutsche Jose Carreras Stiftung e.V. (DJCLS) [R 08/32f]
- German Research Foundation [DFG DO 704/3-1]
- German Research Foundation (Heisenberg-Stipendium) [BU 1339/3-1]
- German Research Foundation
- EU
- [IAP16/8]
Core-binding factor (CBF) leukemias, characterized by translocations t(8;21) or inv(16)/t(16;16) targeting the CBF, constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, about 40% of patients relapse and the current classification system does not fully reflect this clinical heterogeneity. Previously, gene expression profiling (GEP) revealed two distinct CBF leukemia subgroups displaying significant outcome differences and identified apoptotic signaling, MAPKinase signaling and chemotherapy-resistance mechanisms among the most significant differentially regulated pathways. We now tested different inhibitors of the respective pathways in a cell line model (six cell lines reflecting the CBF subgroup-specific gene expression alterations), and found apoptotic signaling to be differentiating between the CBF subgroup models. In accordance, primary samples from newly diagnosed CBF AML patients (n = 23) also showed differential sensitivity to in vitro treatment with a Smac mimetic such as BV6, an antagonist of inhibitor of apoptosis (IAP) proteins, and ABT-737, a BCL2 inhibitor. Furthermore, GEP revealed the BV6-resistant cases to resemble the previously identified unfavorable CBF subgroup. Thus, our current findings show deregulated IAP expression and apoptotic signaling to differentiate clinically relevant CBF subgroups, which were independent of known molecular markers, thereby providing a starting point for novel therapeutic approaches. Leukemia (2011) 25, 1728-1738; doi:10.1038/leu.2011.154; published online 21 June 2011
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