Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia
© 2022. The Author(s)..
Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:32 |
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| Enthalten in: |
Cell research - 32(2022), 12 vom: 27. Dez., Seite 1105-1123 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hu, Cheng-Long [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.12.2022 Date Revised 29.01.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41422-022-00735-6 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM348172206 |
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| 100 | 1 | |a Hu, Cheng-Long |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia |
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| 500 | |a Date Revised 29.01.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Chen, Bing-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zijuan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Tianbiao |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Chun-Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Ruirui |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Peng-Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jingyao |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Na |e verfasserin |4 aut | |
| 700 | 1 | |a Shan, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qunling |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Junhong |e verfasserin |4 aut | |
| 700 | 1 | |a Fei, Ming-Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Zong, Li-Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jia-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Ji-Chuan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shu-Bei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Binhe |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Yilun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiya |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xinchi |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Chu-Han |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Yi-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Roujia |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Jiacheng |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Meirong |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Ling-Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Chun-Kang |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Shuhong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhu |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Sai-Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiaolong |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xiao-Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Mingyue |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lan |e verfasserin |4 aut | |
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