Transcriptomic profiling of MLL-r AML PDX cells treated with CDKI-73 and/or JQ1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA531401 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8864170.fastq.gz | Fastqsanger.gz | |||
| SRR8864171.fastq.gz | Fastqsanger.gz | |||
| SRR8864172.fastq.gz | Fastqsanger.gz | |||
| SRR8864173.fastq.gz | Fastqsanger.gz | |||
| SRR8864174.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptomic profiling of MLL-r AML PDX cells treated with CDKI-73 and/or JQ1
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Project description:The BET (bromodomain and extra terminal) protein family members including BRD4 bind to acetylated lysines on histones and regulate the expression of important oncogenes, e.g., MYC and BCL2. Here we demonstrate the sensitizing effects of the histone hyperacetylation inducing pan-histone deacetylase inhibitor (HDI) panobinostat (PS) on human AML blast progenitor cells (BPCs) to the BET protein inhibitor JQ1. Treatment with JQ1 but not its inactive enantiomer (R-JQ1) was highly lethal against AML BPCs expressing mutant NPM1c+ with or without co-expression of FLT3-ITD, or AML expressing MLL fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of MYC and BCL2, and reduced their levels in the AML cells. Co-treatment with JQ1 and the HDAC inhibitor panobinostat (PS) synergistically induced apoptosis of the AML BPCs, but not of normal CD34+ hematopoietic progenitor cells. This was associated with greater attenuation of MYC and BCL2, while increasing p21, BIM and cleaved PARP levels in the AML BPCs. Co-treatment with JQ1 and PS significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (p < 0.01). These findings highlight co-treatment with a BRD4 antagonist and an HDI as a potentially efficacious therapy of AML. Two samples were analyzed (untreated cells, cells treated with JQ1)
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