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Series GSE42044 Query DataSets for GSE42044
Status Public on Nov 08, 2012
Title DNA methylation changes are a late event in Acute Promyelocytic Leukemia and coincide with loss of transcription factor binding (sequencing)
Organisms Homo sapiens; Mus musculus
Experiment type Methylation profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary The origin of aberrant DNA methylation in cancer remains largely unknown. In this study, we elucidated the DNA methylome in primary Acute Promyelocytic Leukemia (APL) and the role of PML-RARa in establishing these patterns. APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34+ cells, promyelocytes and remission bone marrow. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score and Flt3-mutation status characterized methylation subtypes. Transcription factor binding sites, e.g. c-myc binding sites were associated with low methylation. SUZ12 and REST binding sites identified in embryonic stem cells were, however, preferentially DNA hypermethylated in APL. Unexpectedly, PML-RARa binding sites were also protected from aberrant DNA methylation in APL. In line, myeloid cells from pre-leukemic PML-RARa knock-in mice did not show altered DNA methylation and expression of PML-RARa in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. ATRA treatment of APL blasts did also not result in DNA methylation changes. These results suggest that aberrant DNA methylation is associated with leukemia phenotype but not required for PML-RARa-mediated initiation of leukemogenesis.
 
Overall design We used Reduced Representation Bisulfite Sequencing (RRBS) to determine the genome-wide methylation signature of 18 primary APL patient samples. We then compared the APL methylation signature with methylation patterns found in CD34+ progenitor cells (n=4), promyelocytes (n=4) and remission bone marrow samples (n=8). Differentially methylated regions found in all three comparisons (APL vs. all three control specimens) were then further analyzed for genomic localization, variability and association with clinical parameters. Finally, the relationship between differentially methylated regions in APL and specific transcription factor binding sites was analyzed. For this purpose, ChiP-Sequencing of SUZ12 and REST was performed in primary APL patient blasts. To further determine the contribution of the leukemogenic transcription factor PML-RARa to methylation in APL, we also performed RRBS in pre-leukemic PML-RARa knock-in mice and hematopoetic progenitor cells retrovirally transduced with PML-RARa.
 
Contributor(s) Rohde C, Schoofs T, Müller-Tidow C
Citation(s) 23152544
Submission date Nov 05, 2012
Last update date May 15, 2019
Contact name Christian Rohde
E-mail(s) christian.rohde@uni-heidelberg.de
Organization name Heidelberg University
Lab Molecular Hematology and Oncology
Street address Im Neuenheimer Feld 410
City Heidelberg
ZIP/Postal code 69120
Country Germany
 
Platforms (3)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL15456 Illumina HiScanSQ (Homo sapiens)
GPL16173 Illumina HiScanSQ (Mus musculus)
Samples (51)
GSM1031192 RRBS primary diagnosis APL_5
GSM1031193 RRBS primary diagnosis APL_10545
GSM1031194 RRBS primary diagnosis APL_10892
This SubSeries is part of SuperSeries:
GSE42119 DNA methylation changes are a late event in Acute Promyelocytic Leukemia and coincide with loss of transcription factor binding
Relations
BioProject PRJNA179154
SRA SRP017090

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE42044_RAW.tar 576.9 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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