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| Status |
Public on Aug 14, 2023 |
| Title |
Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment II |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
Decitabine (DAC) is used clinically for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells shows that mitotic regulation plays a pivotal role in DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations and antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, the overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation, while highlighting the potent activity of DAC to perturb mitosis through aberrant DNMT1-DNA covalent bonds.
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| Overall design |
To identify genes that regulate sensitivity and resistance of AML cells to DAC and SAHA, we performed a genome-wide pooled CRISPR activation screen using cSAM (engineered murine sAML (MDS/AML) cells transformed by combined expression of SETBP1 and ASXL1 Mutations cells expressing the Suntag system.
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| Web link |
https://pubmed.ncbi.nlm.nih.gov/37714156/
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| Contributor(s) |
Yabushita T, Kitamura T, Goyama S |
| Citation(s) |
37714156 |
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| Submission date |
Aug 10, 2023 |
| Last update date |
Nov 19, 2023 |
| Contact name |
Tomohiro Yabushita |
| E-mail(s) |
[email protected]
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| Organization name |
The University of Tokyo
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| Street address |
7-3-1, Hongou, Bunkyo-ku
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| City |
Tokyo |
| ZIP/Postal code |
113-8654 |
| Country |
Japan |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA1004250 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE240570_raw_counts.txt.gz |
1.9 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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