WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target

Autor: Haige Ye, Bin Zhou, Shenmeng Gao, Xianghong Jin, Yanfei Wu, Haiying Li, Weijian Zhu, Weiwei Jin, Xiaoyi Qin, Xingzhou Huang
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
congenital
hereditary
and neonatal diseases and abnormalities
lcsh:Medicine
Leukemia stem cell
Mice
SCID
Biology
urologic and male genital diseases
General Biochemistry
Genetics and Molecular Biology
BCL2L2
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
Wilms’ tumor-1
Mice
Inbred NOD
hemic and lymphatic diseases
Ubiquitin–proteasome signal
medicine
Animals
WT1 Proteins
Transcription factor
Deubiquitinase inhibitor
Gene knockdown
urogenital system
Research
lcsh:R
Myeloid leukemia
General Medicine
Leukemia-initiating cell
medicine.disease
female genital diseases and pregnancy complications
Up-Regulation
Leukemia
Leukemia
Myeloid
Acute
030104 developmental biology
030220 oncology & carcinogenesis
Cancer research
NSG mouse
Neoplastic Stem Cells
Self-renewal
Stem cell
Apoptosis Regulatory Proteins
Zdroj: Journal of Translational Medicine
Journal of Translational Medicine, Vol 18, Iss 1, Pp 1-15 (2020)
ISSN: 1479-5876
Popis: Background Overexpression of Wilms’ tumor-1 (WT1) transcription factor facilitates proliferation in acute myeloid leukemia (AML). However, whether WT1 is 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 of wt1 on the self-renewal ability of LSC. RNA sequencing was performed on WT1-overexpressing cells to select WT1 targets. Apoptosis and colony formation assays were used to assess the anti-leukemic potential of a deubiquitinase inhibitor WP1130. Furthermore, NOD/SCID-IL2Rγ (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 that wt1 is 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 of BCL2L2, a member of B cell lymphoma 2 (BCL2) family, by direct binding to its promoter region. Loss of WT1 impaired 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 that WT1 is 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.
Databáze: OpenAIRE
Externí odkaz: