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A noncanonical Flt3ITD/NF-kappaB signaling pathway represses DAPK1 in acute myeloid leukemia Shanmugam R; Gade P; Wilson-Weekes A; Sayar H; Suvannasankha A; Goswami C; Li L; Gupta S; Cardoso AA; Baghdadi TA; Sargent KJ; Cripe LD; Kalvakolanu DV; Boswell HSClin Cancer Res 2012[Jan]; 18 (2): 360-369PURPOSE: 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-kappaB-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-kappaB, 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-kappaB. Chromatin immunoprecipitation assays identified p52NF-kappaB 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-kappaB or its upstream regulator, NF-kappaB-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD(+) AMLs had selective nuclear activation of p52NF-kappaB. CONCLUSIONS: Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-kappaB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD(+) AML.|*Signal Transduction[MESH]|Apoptosis[MESH]|Apoptosis Regulatory Proteins/genetics/*metabolism[MESH]|Binding Sites[MESH]|Calcium-Calmodulin-Dependent Protein Kinases/genetics/*metabolism[MESH]|DNA Methylation[MESH]|Death-Associated Protein Kinases[MESH]|Epigenesis, Genetic[MESH]|Gene Expression Profiling[MESH]|Gene Expression Regulation, Leukemic[MESH]|HL-60 Cells[MESH]|Humans[MESH]|Karyotype[MESH]|Leukemia, Myeloid, Acute/genetics/*metabolism[MESH]|MAP Kinase Kinase Kinases/metabolism[MESH]|Mutation[MESH]|NF-kappa B p52 Subunit/*metabolism[MESH]|Promoter Regions, Genetic[MESH]|Protein Binding[MESH]|Tandem Repeat Sequences[MESH]|Tumor Cells, Cultured[MESH]|fms-Like Tyrosine Kinase 3/genetics/*metabolism[MESH] |
