|
|
GEO help: Mouse over screen elements for information. |
|
Status |
Public on May 03, 2021 |
Title |
Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
|
Summary |
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P<0.0001). In particular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experiments. The patients displayed enrichment in gene signatures regulated by methylation and modifiable by decitabine administration, shared common H3K27-acetylated regions, and had a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5’-azacytidine and decitabine in controlling disease progression in vivo.
|
|
|
Overall design |
Molecular characterization of BPDCN cases by Whole-Exome and RNA sequencing.
|
|
|
Contributor(s) |
Sapienza MR, Abate F, Tripodo C, Rabadan R, Pileri SA |
Citation(s) |
30381297, 34572907 |
Submission date |
Jan 15, 2021 |
Last update date |
Oct 06, 2021 |
Contact name |
Raul Rabadan |
E-mail(s) |
rr2579@cumc.columbia.edu
|
Organization name |
Columbia University
|
Street address |
622 W 168th St
|
City |
New York |
State/province |
NY |
ZIP/Postal code |
10032 |
Country |
USA |
|
|
Platforms (1) |
GPL15456 |
Illumina HiScanSQ (Homo sapiens) |
|
Samples (13)
|
|
Relations |
BioProject |
PRJNA692486 |
SRA |
SRP301976 |
Supplementary file |
Size |
Download |
File type/resource |
GSE164939_RNASeq.rawcounts.txt.gz |
648.5 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
Raw data are available in SRA |
Processed data are available on Series record |
|
|
|
|
|