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Series GSE102947 Query DataSets for GSE102947
Status Public on May 30, 2018
Title SETDB2 links E2A-PBX1 to cell cycle dysregulation in acute leukemia through CDKN2C repression [sequencing]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality necessitating further improvements in diagnosis and therapy. Targeted therapies directed against epigenetic regulators, which are frequently mutated or misregulated in acute leukemia, are emerging as candidate approaches in preclinical studies and early trials. However, the epigenetic factors involved in most ALLs are not well defined or functionally characterized. In this study, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is over-expressed in a wide spectrum of leukemias, required for their maintenance in vitro and in vivo, and its elevated expression correlates with a poor prognosis in clinical cohorts. In a subset of ALL with the preBCR+ phenotype, SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1. In this subset, SETDB2 epigenetically suppresses expression of the cell cycle inhibitor CDKN2C through histone H3K9 tri-methylation thus establishing a novel oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. In addition to targeting SETDB2 alone, its knockdown significantly enhanced sensitivity to kinase and epigenetic inhibitors suggesting a potential approach to future combination treatments. Our studies define an epigenetic role for SETDB2 in leukemia pathogenesis, and provide a mechanistic rationale for targeting SETDB2 therapeutically in a subset of leukemia.
Overall design For RNAseq experiment, E2A-PBX1 was specifically knocked down by two shRNAs in two human E2A-PBX1+ cell lines (RCH-ACV, 697). Finally, two cell lines with two shRNAs plus corresponding control in triplicates are submitted to RNAseq sequencing. For ChIP-seq, RCH-ACV cells depleted of SETDB2 by shRNA were immuoprecipitated with anti-H3K9me3 antibody, and together with input control were constructed for ChIP-seq libraries and submitted to single-end ChIP-sequencing (detailed protocol referred to, Wong et al., 2015, Cancer Cell).
Contributor(s) Wong SH, Lin C, Cleary ML, Kurzer JH, Schneidawind C, Wei MC, Duque-Afonso J, Jeong J
Citation(s) 29694893
Submission date Aug 22, 2017
Last update date Jul 25, 2021
Contact name Stephen HK WONG
Phone 6507235340
Organization name Stanford University
Department Pathology
Lab Dr. Michael Cleary
Street address G2035 SIM1 Bldg
City Stanford
State/province California
ZIP/Postal code 94305
Country USA
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (22)
GSM2750969 shRNA1-697-A
GSM2750970 shRNA1-697-B
GSM2750971 shRNA1-697-C
This SubSeries is part of SuperSeries:
GSE125334 SETDB2 links E2A-PBX1 to cell cycle dysregulation in acute leukemia through CDKN2C repression
BioProject PRJNA399516
SRA SRP115954

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SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE102947_ALL.RNAseq.expr.FPKM.txt.gz 2.9 Mb (ftp)(http) TXT
GSE102947_ALL.RNAseq.raw.count.txt.gz 573.5 Kb (ftp)(http) TXT
GSE102947_DESeq2.DEG.shRNA1.697.txt.gz 1.1 Mb (ftp)(http) TXT
GSE102947_DESeq2.DEG.shRNA1.RCHACV.txt.gz 1.1 Mb (ftp)(http) TXT
GSE102947_DESeq2.DEG.shRNA2.697.txt.gz 1.1 Mb (ftp)(http) TXT
GSE102947_DESeq2.DEG.shRNA2.RCHACV.txt.gz 1.1 Mb (ftp)(http) TXT
GSE102947_RAW.tar 4.0 Gb (http)(custom) TAR (of BEDGRAPH, BIGWIG, TXT)
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Raw data are available in SRA
Processed data are available on Series record
Processed data provided as supplementary file

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