Journal
JOURNAL OF TRANSLATIONAL MEDICINE
Volume 18, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12967-020-02384-y
Keywords
Leukemia-initiating cell; Leukemia stem cell; Deubiquitinase inhibitor; Ubiquitin-proteasome signal; Wilms' tumor-1; Self-renewal
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Funding
- National Natural Science Foundation of China [81672087, 81971991]
- Zhejiang Provincial Natural Science Foundation of China [LY19H080001]
- Wenzhou Municipal Sci-Tech Bureau's program [Y20180218]
- Medical Health Science and Technology Project of Zhejiang Provincial Health Commission [2019KY452]
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Background Overexpression of Wilms' tumor-1 (WT1) transcription factor facilitates proliferation in acute myeloid leukemia (AML). However, whetherWT1is enriched in the leukemia-initiating cells (LICs) and leukemia stem cells (LSCs) and facilitates the self-renewal of LSCs remains poorly understood. Methods MLL-AF9-induced murine leukemia model was used to evaluate the effect of knockdown ofwt1on the self-renewal ability of LSC. RNA sequencing was performed onWT1-overexpressing cells to selectWT1targets. Apoptosis and colony formation assays were used to assess the anti-leukemic potential of a deubiquitinase inhibitor WP1130. Furthermore, NOD/SCID-IL2R gamma (NSG) AML xenotransplantation and MLL-AF9-induced murine leukemia models were used to evaluate the anti-leukemogenic potential of WP1130 in vivo. Results We found thatwt1is highly expressed in LICs and LSCs and facilitates the maintenance of leukemia in a murine MLL-AF9-induced model of AML. WT1 enhanced the self-renewal of LSC by increasing the expression ofBCL2L2, a member ofB cell lymphoma 2(BCL2) family, by direct binding to its promoter region. Loss ofWT1impaired self-renewal ability in LSC and delayed the progression of leukemia. WP1130 was found to modify the WT1-BCL2L2 axis, and WP1130-induced anti-leukemic activity was mediated by ubiquitin proteasome-mediated destruction of WT1 protein. WP1130 induced apoptosis and decreased colony formation abilities of leukemia cells and prolonged the overall survival in the THP1-based xenograft NSG mouse model. WP1130 also decreased the frequency of LSC and prolonged the overall survival in MLL-AF9-induced murine leukemia model. Mechanistically, WP1130 induced the degradation of WT1 by positively affecting the ubiquitination of WT1 protein. Conclusions Our results indicate thatWT1is required for the development of AML. WP1130 exhibits anti-leukemic activity by inhibiting the WT1-BCL2L2 axis, which may represent a new acute myeloid leukemia therapy target.
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