Deletion of the Hoxa Cluster in MLL-AF9 Is Incompatible with Leukemia Maintenance: RNAseq-based Quantitative Analysis of Wild Type and Hoxa-del Transcriptomes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA450411 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7010870_1.fastq.gz | Fastqsanger.gz | |||
| SRR7010870_2.fastq.gz | Fastqsanger.gz | |||
| SRR7010880_1.fastq.gz | Fastqsanger.gz | |||
| SRR7010880_2.fastq.gz | Fastqsanger.gz | |||
| SRR7010871_1.fastq.gz | Fastqsanger.gz |
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Project description:MIR139 is a critical tumor suppressor and commonly silenced in human cancer, including acute myeloid leukemia (AML). Here, we found that depletion of identified MIR139 targets affects AML outgrowth. We unraveled the mechanism of MIR139 gene inactivation in AML expressing the Mixed-Lineage Leukemia (MLL)-AF9 oncogene. Epigenetic analyses revealed two well-conserved putative enhancer regions in close proximity of transcriptional start sites (TSS) of MIR139. These regions were silenced by the Polycomb-Repressive Complex-2 (PRC2) downstream of MLL-AF9. Genomic deletion of these regions abolished MIR139 transcriptional regulation in normal and oncogenic conditions. Genome-wide knockout screens revealed the transcriptional pausing factor of RNA Polymerase-II, POLR2M, as a critical MIR139-silencing factor. Furthermore, direct POLR2M binding to the MIR139 TSS induced paused transcription, which was abrogated upon PRC2 inhibition. We present evidence for an oncogenic POLR2M-mediated MIR139 silencing mechanism, downstream of MLL-AF9 and PRC2. Together, our findings highlight the importance of POLR2M-mediated paused transcription in AML.
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