USP10 modulates the SKP2/Bcr-Abl axis via stabilizing SKP2 in chronic myeloid leukemia

Yuning Liao,Zhiqiang Guo,Yanling Li,Ningning Liu,Ruiqing Zhou,Xiaohong Xia,Jinbao Liu,Hongbiao Huang,Daolin Tang,Lili Jiang

doi:10.1038/s41421-019-0092-z

Abstract

Constitutive activation of tyrosine kinase Bcr-Abl is the leading cause of the development and progression of chronic myeloid leukemia (CML). Currently, the application of tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl is the primary therapy for CML patients. However, acquired resistance to TKIs that develops overtime in the long-term administration renders TKIs ineffective to patients with advanced CML. Therefore, increasing studies focus on the amplified expression or activation of Bcr-Abl which is proposed to contribute to the advanced phase. Here, we show that S-phase kinase-associated protein 2 (SKP2) acts as a co-regulator of Bcr-Abl by mediating its K63-linked ubiquitination and activation. Further investigations show that USP10 as a novel deubiquitinase of SKP2 amplifies the activation of Bcr-Abl via mediating deubiquitination and stabilization of SKP2 in CML cells. Moreover, inhibition of USP10 significantly suppresses the proliferation of both imatinib-sensitive and imatinib-resistant CML cells, which likely depends on SKP2 status. This findings are confirmed in primary CML cells because these cells are over-expressed with USP10 and SKP2 and are sensitive to a USP10 inhibitor. Taken together, the present study not only provides a novel insight into the amplified activation of Bcr-Abl in CML, but also demonstrates that targeting the USP10/SKP2/Bcr-Abl axis is a potential strategy to overcome imatinib resistance in CML patients.

Highlights

Chronic myeloid leukemia (CML), a hematopoietic malignancy, is caused by constitutively high autophosphorylation of the oncogenic tyrosine kinase Bcr-Abl that results from the translocation of t(9;22)(q34;q11)[1,2]
Bcr-Abl enhances mRNA expression of S-phase kinase-associated protein 2 (SKP2) via the PI3K/AKT/Sp1 pathway[9]; on the other hand, BcrAbl inhibits APC/Cdh[1] to stabilize SKP2 via inducing tyrosine phosphorylation of Emi[1], a negative regulator of the APC/Cdh ligase[10]. We verified this interaction in two typical CML cell lines: the wild-type KBM5 and KBM5-T315I that bears the T315I mutation
Compared to KBM5-T315I, KBM5 cells were more sensitive to IM treatment, and the decreased phosphorylation levels of Bcr-Abl and SKP2 protein level by IM was more dramatic than that in KBM5-T315I cells, suggesting that the alteration of SKP2 is consistent with the level of phosphorylated Bcr-Abl (Fig. 1a, b)

Summary

Introduction

Chronic myeloid leukemia (CML), a hematopoietic malignancy, is caused by constitutively high autophosphorylation of the oncogenic tyrosine kinase Bcr-Abl that results from the translocation of t(9;22)(q34;q11)[1,2]. Bcr-Abl contributes to the tumorigenesis of CML by activating multiple signaling pathways, including MAPK/ ERK, PI3K/Akt, JNK, STAT5, and SRC3–7. Among the mechanisms underlying CML resistance to imatinib, the T315I mutation of Bcr-Abl is the most notorious; even the most potent TKIs are ineffective to patients with the T315I mutation because this mutation. An early study demonstrated that SKP2 promotes G1 to S phase transition via enhancing ubiquitin-dependent proteasomal degradation of p2724. Recent studies showed that SKP2 promotes tumorigenesis via mediating the ubiquitination of FOXO125, and Akt[26], or suppressing cellular senescence[27]. The roles of SKP2 and mechanisms regulating its protein level in CML remain largely unclear

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Results

Conclusion