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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 01, 2022 |
| Title |
Non-toxic direct targeted therapy for MLL-fusion driven leukemias |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Improving the poor prognosis of infant leukemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven pediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL-fusion oncoproteins. A screen for inhibition of MLL-fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter-based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, Disulfiram, based on its efficient ablation of MLL fusion proteins. The consequences of drug-induced MLL-fusion inhibition was confirmed by cell proliferation, colony formation, apoptosis assays, RT-qPCR, in vivo assays, RNA-seq and CHIP-qPCR and CHIP-seq analysis. All statistical tests were two-sided. Drug-induced inhibition of MLL-fusion proteins by Disulfiram resulted in a specific block of colony formation in MLL-rearranged cells in vitro, induced differentiation and impeded leukemia progression in vivo. Mechanistically, Disulfiram abrogates MLL-fusion protein binding to DNA, resulting in epigenetic changes and down-regulation of leukemic programs setup by the MLL-fusion protein. Disulfiram can directly inhibit MLL-fusion proteins and demonstrates antitumor activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly target the initiating oncogenic MLL-fusion protein.
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| Overall design |
RNA sequencing of THP-1 cells untreated or treated with DSF, combined with ChIP-seq data of MLL, H3K4me3 and H3K27ac
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| Contributor(s) |
Cantilena S, Gasparoli L, Pal D, Heidenreich O, Klusmann J, Martens JH, Faille A, Warren AJ, Karsa M, Pandher R, Somers K, Williams O, de Boer J |
| Citation(s) |
35730653 |
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| Submission date |
May 17, 2022 |
| Last update date |
Aug 02, 2022 |
| Contact name |
Joost Martens |
| E-mail(s) |
j.martens@science.ru.nl
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| Phone |
0243780645
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| Organization name |
Radboud University
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| Department |
RIMLS
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| Lab |
Molecular Biology
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| Street address |
Geert Grooteplein 28
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| City |
Nijmegen |
| State/province |
Nederland |
| ZIP/Postal code |
6525GA |
| Country |
Netherlands |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (16)
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| GSM6161724 |
THP1-DSF-3-16H_S10,RNA-seq |
| GSM6161725 |
THP1-DSF-4-16H_S11,RNA-seq |
| GSM6161726 |
THP1-DSF-6-16H_S12,RNA-seq |
| GSM6161727 |
THP1-CTRL-H3K27_S2,ChIP-seq |
| GSM6161728 |
THP1-CTRL-H3K27_S4,ChIP-seq |
| GSM6161729 |
THP1-CTRL-H3K4_S6,ChIP-seq |
| GSM6161730 |
THP1-CTRL-H3K4_S8,ChIP-seq |
| GSM6161731 |
THP1-CTRL-MLL_S10,ChIP-seq |
| GSM6161732 |
THP1-DSF-H3K27_S1,ChIP-seq |
| GSM6161733 |
THP1-DSF-H3K27_S3,ChIP-seq |
| GSM6161734 |
THP1-DSF-H3K4_S5,ChIP-seq |
| GSM6161735 |
THP1-DSF-H3K4_S7,ChIP-seq |
| GSM6161736 |
THP1-DSF-MLL_S9,ChIP-seq |
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| Relations |
| BioProject |
PRJNA839020 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE203203_GRCh38-counts.tsv.gz |
276.3 Kb |
(ftp)(http) |
TSV |
| GSE203203_RAW.tar |
1.1 Gb |
(http)(custom) |
TAR (of BIGWIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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