期刊
CLINICAL CANCER RESEARCH
卷 18, 期 2, 页码 360-369出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-3022
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资金
- Department of Veterans Affairs
- NIH [CA78282]
Purpose: Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis. Experimental Design: Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-kappa B-and c-Jun-responsive genes, was studied. RNA interference knockdown studies were carried out in an Flt3ITD(+) cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were carried out to identify proximate effector proteins, including TAK1-activated p52NF-kappa B, at the DAPK1 locus. Results: AMLs characterized by normal karyotype with Flt3ITD were found to have 10- to 100-fold lower DAPK1 transcripts normalized to the expression of c-Jun, a transcriptional activator of DAPK1, as compared with a heterogeneous cytogenetic category. In addition, Meis1, a c-Jun-responsive adverse AML prognostic gene signature was measured as control. These Flt3ITD(+) AMLs overexpress relB, a transcriptional repressor, which forms active heterodimers with p52NF-kappa B. Chromatin immunoprecipitation assays identified p52NF-kappa B binding to the DAPK1 promoter together with histone deacetylase 2 (HDAC2) and HDAC6 in the Flt3ITD(+) human AML cell line MV-4-11. Knockdown of p52NF-kappa B or its upstream regulator, NF-kappa B-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD(+) AMLs had selective nuclear activation of p52NF-kB. Conclusions: Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-kappa B to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD(+) AML. Clin Cancer Res; 18(2); 360-9. (C) 2011 AACR.
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