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| Status |
Public on Aug 29, 2023 |
| Title |
SUMOylation inhibitor TAK-981 (Subasumstat) synergizes with 5-azacitidine in preclinical models of acute myeloid leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Acute Myeloid Leukemias (AML) are severe hematomalignancies with dismal prognosis. The post-translational modification SUMOylation plays key roles in leukemogenesis and AML response to therapies. Here, we show that TAK-981 (subasumstat), a first-in-class SUMOylation inhibitor, is endowed with potent anti-leukemic activity in various preclinical models of AML. TAK-981 targets AML cell lines and patient blast cells in vitro and in vivo in xenografted mice with minimal toxicity on normal hematopoietic cells. Moreover, it synergizes with 5-azacitidine (AZA), a DNA-hypomethylating agent now used in combination with the BCL-2 inhibitor venetoclax to treat AML patients unfit for standard chemotherapies. Interestingly, TAK-981+AZA combination shows higher anti-leukemic activity than AZA+venetoclax combination both in vitro and in vivo, at least in the models tested. Mechanistically, TAK-981 potentiates the transcriptional reprogramming induced by AZA, promoting apoptosis, alteration of the cell cycle and differentiation of the leukemic cells. In addition, TAK-981+AZA treatment induces many genes linked to inflammation and immune response pathways. In particular, this leads to the secretion of type I interferon (IFN-I) by AML cells. Finally, TAK-981+AZA induces the expression of Natural Killer (NK)-activating ligands (MICA/B) and adhesion proteins (ICAM-1) at the surface of AML cells. Consistently, TAK-981+AZA-treated AML cells activate NKs and increase their cytotoxic activity. Targeting SUMOylation with TAK-981 may thus be a promising strategy to both sensitize AML cells to AZA and reduce their immune-escape capacities.
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| Overall design |
Total RNA from U937 cells treated for 3 days with 10nM of either TAK-981, 5-azacitidine or the combination of TAK-981 + 5-azacitidine were sequenced in 3 biological replicates.
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| Contributor(s) |
Bossis G, Tempé D |
| Citation(s) |
37608777 |
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| Submission date |
Aug 30, 2022 |
| Last update date |
Aug 29, 2023 |
| Contact name |
Denis Tempé |
| E-mail(s) |
denis.tempe@igmm.cnrs.fr
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| Organization name |
CNRS
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| Lab |
IGMM
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| Street address |
1919 route de Mende
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| City |
Montpellier |
| ZIP/Postal code |
34293 |
| Country |
France |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA875058 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE212330_suppTable2_DESeq2.csv.gz |
8.7 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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