Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

JMJD1C is required for the survival of acute myeloid leukemia by functioning as a co-activator for key transcription factors

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Mo Chen

PROVIDER: E-GEOD-63486 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors.

Chen Mo M Zhu Nan N Liu Xiaochuan X Laurent Benoit B Tang Zhanyun Z Eng Rowena R Shi Yang Y Armstrong Scott A SA Roeder Robert G RG

Genes & development 20151001 20

RUNX1-RUNX1T1 (formerly AML1-ETO), a transcription factor generated by the t(8;21) translocation in acute myeloid leukemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting differentiation. Here we demonstrate that the histone demethylase JMJD1C functions as a coactivator for RUNX1-RUNX1T1 and is required for its transcriptional program. JMJD1C is directly recruited by RUNX1-RUNX1T1 to its target genes and regulates their expression by maintaining low H3K9 dimethyl (H3 ...[more]

PMID: 26494788

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Project description:Neuroblastoma tumors frequently show loss of heterozygosity of chromosome 11q with a shortest region of overlap in the 11q23 region. These deletions are thought to cause inactivation of tumor suppressor genes leading to haploinsufficiency. Alternatively, micro-deletions could lead to gene fusion products that are tumor-driving. To identify such events we analyzed a series of neuroblastomas by comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays and integrated these data with Affymetrix mRNA profiling data with the bioinformatic tool R2 (http://r2.amc.nl). We identified three neuroblastoma samples with small interstitial deletions at 11q23, upstream of the forkhead-box transcription factor FOXR1. Genes at the proximal side of the deletion were fused to FOXR1, resulting in fusion transcripts of MLL-FOXR1 and PAFAH1B2-FOXR1. FOXR1 expression has only been detected in early embryogenesis. Affymetrix microarray analysis showed high FOXR1 mRNA expression exclusively in the neuroblastomas with micro-deletions and rare cases of other tumor types, including osteosarcoma cell line HOS. RNAi silencing of FOXR1 strongly inhibited proliferation of HOS cells and triggered apoptosis. Expression profiling of these cells and reporter assays suggested that FOXR1 is a negative regulator of forkhead-box factor mediated transcription. The neural crest stem cell line JoMa1 proliferates in culture conditional to activity of a MYC-ER transgene. Over-expression of the wild-type FOXR1 could functionally replace MYC and drive proliferation of JoMa1. We conclude that FOXR1 is recurrently activated in neuroblastoma by intrachromosomal deletion/fusion events, resulting in over-expression of fusion transcripts. Forkhead-box transcription factors have not been previously implicated in neuroblastoma pathogenesis. Furthermore, this is the first identification of intrachromosomal fusion genes in neuroblastoma. Time series Affymetrix U133p2 profiling of Osteosarcoma HOS cells transduced with FOXR1 targeted shRNAs or control shRNA

Dataset Information

JMJD1C is required for the survival of acute myeloid leukemia by functioning as a co-activator for key transcription factors

Publications

JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors.

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