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Series GSE85988 Query DataSets for GSE85988
Status Public on Nov 23, 2016
Title MLL-AF4 binds directly to a BCL-2 specific enhancer and impacts H3K27 acetylation
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Survival rates for children diagnosed with acute lymphoblastic leukemia (ALL) have drastically improved, but those carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in ALL is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we showed that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. We went on to show that MLL leukemias are particularly sensitive to treatment with the BCL-2 inhibitor venetoclax which synergizes with both standard chemotherapeutic agents as well as DOT1L inhibitors. Altered expression of other BCL-2 family members is a major cause of resistance to ventoclax, so here we perform a detalied analysis of MLL-AF4 regulation of the entire BCL-2 family. By measuring nascent RNA production, we find that of all the BCL-2 family genes, MLL-AF4 directly controls the transcription of both BCL-2 and MCL-1, but only BCL-2 shows a significant loss of steady state RNA levels. Interestingly however, both MCL-1 and BCL-XL protein levels are dependent on MLL-AF4 activity through an unknown and likely indirect mechanism. Finally, we analyze MLL-AF4 regulation of the BCL-2 gene in greater detail and using Capture C we identify a major BCL-2 specific enhancer consisting of two clusters of H3K27Ac. Loss of MLL-AF4 activity results in a reduction of H2K27Ac levels at the major BCL-2 enhancer, revealing a novel regulatory dependence on MLL-AF4 function at BCL-2.
Overall design Examination of MLL-AF4-mediated regulation at BCL2-family genes using nascent RNA-seq to observe gene expression changes following siRNA-mediated knockdown and treatment with the DOT1L inhibitor EPZ-5676. We also investigated changes in histone mark occupancy at the BCL2 promoter and enhancer following siRNA-mediated knockdown of MLL-AF4
Contributor(s) Milne TA, Kerry J
Citation(s) 27856324
Submission date Aug 24, 2016
Last update date May 15, 2019
Contact name Thomas Milne
Organization name Weatherall Institute of Molecular Medicine
Department Molecular Haematology Unit
Street address John Radcliffe Hospital
City Oxford
ZIP/Postal code OX3 9DS
Country United Kingdom
Platforms (2)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (21)
GSM2290160 SEM_siControl_Rep1
GSM2290161 SEM_siControl_Rep2
GSM2290162 SEM_siControl_Rep3
BioProject PRJNA339938
SRA SRP082679

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Supplementary file Size Download File type/resource
GSE85988_EPZ5676_rpkm.txt.gz 527.4 Kb (ftp)(http) TXT
GSE85988_RAW.tar 1.5 Gb (http)(custom) TAR (of BW, TXT)
GSE85988_siMLLAF4_rpkm.txt.gz 507.5 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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