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| Status |
Public on Feb 09, 2022 |
| Title |
Deacetylation of YAP1 promotes the resistance to chemo-and targeted therapy in FLT3-ITD + AML cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The FLT3-ITD mutation occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor prognosis. However, FLT3 inhibitors are only partially effective and prone to acquired resistance. Here, we identified Yes-associated protein 1 (YAP1) as a tumor suppressor in FLT3-ITD+ AML. YAP1 inactivation conferred FLT3-ITD+ AML cells resistance to chemo- and targeted therapy. Mass spectrometric assay revealed DNA damage repair gene poly (ADP-ribose) polymerase 1 (PARP1) might be the downstream of YAP1, and the pro-proliferative effect by YAP1 knockdown were partly reversed via PARP1 inhibitor. Importantly, histone deacetylase 10 (HDAC10) contributed to decreased YAP1 acetylation levels through histone H3 lysine 27 (H3K27) acetylation, leading to the reduced nuclear accumulation of YAP1. Selective HDAC10 inhibitor chidamide or HDAC10 knockdown activated YAP1, enhanced DNA damage and significantly attenuated FLT3-ITD+ AML cells resistance. Additionally, combination chidamide with FLT3 inhibitors or chemotherapy agents synergistically inhibited growth and increased apoptosis of FLT3-ITD+AML cell lines and acquired resistant cells from the relapse FLT3-ITD+ AML patients. These findings demonstrate that the HDAC10-YAP1-PARP1 axis maintains FLT3-ITD+ AML cells and targeting this axis might improve clinical outcomes in FLT3-ITD+ AML patients._x001F__x001F__x001F__x001F_
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| Overall design |
Gene expression analysis by RNA-seq of MV4-11 cells（existing FLT3-ITD mutation) treated with 10 nM sorafenib for 24 days.MV4-11 cells were collected in Trizol for RNA-Sequence at Day 0, Day 6,Day 12,Day 18,Day 24.
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| Contributor(s) |
Feng P, Zhang J, Ye J, Ji C |
| Citation(s) |
35656547 |
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| Submission date |
Feb 07, 2022 |
| Last update date |
Jun 21, 2022 |
| Contact name |
Chunyan Ji |
| Organization name |
Qilu Hospital
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| Street address |
Wenhua West Road
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| City |
Jinan |
| ZIP/Postal code |
250000 |
| Country |
China |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (5)
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| Relations |
| BioProject |
PRJNA804105 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE196258_all_compare.txt.gz |
7.7 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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