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

Bin Zhou,Xianghong Jin,Haige Ye,Shenmeng Gao,Xingzhou Huang,Weijian Zhu,Weiwei Jin,Yanfei Wu,Xiaoyi Qin,Haiying Li

doi:10.1186/s12967-020-02384-y

Abstract

BackgroundOverexpression 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.MethodsMLL-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.ResultsWe 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.ConclusionsOur 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.

Highlights

Overexpression of Wilms’ tumor-1 (WT1) transcription factor facilitates proliferation in acute myeloid leukemia (AML)
Our results indicate that WT1 is required for the development of AML
WT1 is required for the development of AML, and treatment with WP1130 might represent a useful therapeutic modality for AML patients by affecting the WT1-BCL2L2 axis

Summary

Introduction

Overexpression of Wilms’ tumor-1 (WT1) transcription factor facilitates proliferation in acute myeloid leukemia (AML). Acute myeloid leukemia (AML) is a fatal hematological malignancy characterized by the differentiation block and overproliferation of leukemic blasts. AML initiates from a small subset of leukemia stem cells (LSCs) that are responsible for chemotherapy resistance and relapse in AML patients [1]. WT1 plays an important role in development, differentiation arrest, apoptosis, and proliferation [8].Overexpression of WT1 enhances cell proliferation and inhibits apoptosis through transcriptional activation of multiple oncogenes, such as B-cell lymphoma-2 (BCL2) [9] and cyclin D1 [10], and transcriptional repression of tumor suppressors, such as E-cadherin [11] and cell division cycle 73 [12]. The molecular mechanism by which WT1 facilitates the proliferation and selfrenewal of LSCs remains to be elucidated

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Discussion

Conclusion