期刊
ONCOTARGET
卷 6, 期 25, 页码 21395-21405出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4095
关键词
FLT3; FLT3-ITD; AML; apoptosis; AKT
资金
- Kungliga Fysiografiska Sallskapet i Lund
- Ollie and Elof Ericssons Stiftelse
- Ake Wiberg Stiftelse
- Lars Hiertas Minne Stiftelse
- Stiftelsen Olle Engkvist Byggmastare
- Harald Jeanssons Stiftelse
- Harald och Greta Jeanssons Stiftelse
- Swedish Childhood Cancer Foundation
- BioCARE cancer network
- Swedish Cancer Society
- Swedish Research Council
- Gunnar Nilssons Cancer Foundation
- Research Grants Council of Hong Kong [N_CUHK413/12]
Acute myeloid leukemia (AML) is a heterogeneous disease of the myeloid lineage. About 35% of AML patients carry an oncogenic FLT3 mutant making FLT3 an attractive target for treatment of AML. Major problems in the development of FLT3 inhibitors include lack of specificity, poor response and development of a resistant phenotype upon treatment. Further understanding of FLT3 signaling and discovery of novel regulators will therefore help to determine additional pharmacological targets in FLT3-driven AML. In this report, we identified BEX1 as a novel regulator of oncogenic FLT3-ITD-driven AML. We showed that BEX1 expression was down-regulated in a group of AML patients carrying FLT3-ITD. Loss of BEX1 expression resulted in poor overall survival (hazard ratio, HR = 2.242, p = 0.0011). Overexpression of BEX1 in mouse pro-B and myeloid cells resulted in decreased FLT3-ITD-dependent cell proliferation, colony and tumor formation, and in increased apoptosis in vitro and in vivo. BEX1 localized to the cytosolic compartment of cells and significantly decreased FLT3-ITD-induced AKT phosphorylation without affecting ERK1/2 or STAT5 phosphorylation. Our data suggest that the loss of BEX1 expression in FLT3-ITD driven AML potentiates oncogenic signaling and leads to decreased overall survival of the patients.
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