Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

Hu, Lei; Xu, Hanzhang; Shan, Huizhuang; Liu, Meng; Lu, Ying; Fang, Zhixiao; Jin, Jin; Jing, Bo; Xiao, Xinhua; Gao, Shenmeng; Gao, Feng‐Hou; Li, Xia; Yang, Li; Liu, Ligen; Wang, Weiwei; Liu, Chuanxu; Yin, Tong; Wu, Yunzhao; Zheng, Junke; Chen, Guoqiang; Zhou, Li; Wu, Yingli

doi:10.1038/s41467-020-20259-0

Cited by 43 publications

(37 citation statements)

References 66 publications

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“…Additionally, P22077 eliminated leukemia stem/progenitor cells in CML mice while exhibiting low toxicity to mononuclear cells in normal peripheral blood. Therefore, targeting USP47 is an effective and secure strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells (Lei et al, 2021).…”

Section: Other Cancersmentioning

confidence: 99%

Role of Ubiquitin-Specific Peptidase 47 in Cancers and Other Diseases

Pan

2021

Front. Cell Dev. Biol.

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Deubiquitination is the reverse process of ubiquitination, which is catalyzed by deubiquitinase enzymes. More than 100 deubiquitinases have been identified. Ubiquitin-specific peptidase 47 (USP47), a member of the ubiquitin-specific protease family with high homology to USP7, is an active molecule with a wide range of functions and is closely associated with cancer and other diseases. However, no systematic summary exists regarding the functions of USP47. Here, we summarize the functions and expression regulation of USP47. USP47 is highly expressed in many tumors and is widely involved in tumor development, metastasis, drug resistance, epithelial-mesenchymal transition, and other processes. Targeted inhibition of USP47 can reverse malignant tumor behavior. USP47 also plays a role in inflammatory responses, myocardial infarction, and neuronal development. USP47 is involved in multiple levels of expression-regulating mechanisms, including transcriptional, post-transcriptional, and post-translational modifications. Development of targeted inhibitors against USP47 will provide a basis for studying the mechanisms of USP47 and developing therapeutic strategies for cancers and other diseases.

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Section: Other Cancersmentioning

confidence: 99%

Role of Ubiquitin-Specific Peptidase 47 in Cancers and Other Diseases

Pan

2021

Front. Cell Dev. Biol.

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“…A few examples of pharmacological DUB inhibitors inducing protein degradation for therapeutic benefit have been reported in hematologic malignancy models, including myeloid neoplasms [265,[352][353][354] and multiple myeloma [353,355,356]. In AML, a recent study showed promising results for destabilization of the FLT3 mutant driver oncoprotein through inhibition of USP10.…”

Section: Are Dubs Possible Therapeutic Targets?mentioning

confidence: 99%

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Barabino

Citterio

2021

Cancers

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Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention.

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“…Delightfully, most of the CML patients can achieve complete remission after receiving tyrosine kinase inhibitors (TKIs) treatment, and some patients even discontinue the TKIs treatment to achieve treatment-free remission (TFR) [ 21 , 22 ]. However, drug resistance and relapse restrict the application of TKIs in treating CML through BCR-ABL-dependent and -independent mechanism [ 23 ]. The BCR-ABL-dependent mechanism is mediated through BCR-ABL gene amplification, mutation of the ABL kinase domain and MDR1 upregulation [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…USP47 is involved in cell survival [ 46 ], cell proliferation [ 47 , 48 ], DNA damage repair [ 23 , 49 , 50 ], epithelial-mesenchymal transition [ 51 ], and inflammation [ 52 , 53 ]. It is demonstrated that Usp47 knockout significantly prolongs the survival of BCR-ABL and BCR-ABL T315I -induced CML mice by reducing leukemia stem/progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

“…It is demonstrated that Usp47 knockout significantly prolongs the survival of BCR-ABL and BCR-ABL T315I -induced CML mice by reducing leukemia stem/progenitor cells. Mechanism studies have shown that USP47 deubiquitinates and stabilizes Y-box binding protein 1(YB-1) and participates in DNA damage repair in CML cells [ 23 ]. It is indicated that USP47 is required for BCR-ABL-induced CML and can overcome BCR-ABL-independent drug resistance.…”

Section: Introductionmentioning

confidence: 99%

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Deubiquitinases in hematological malignancies

Wang

et al. 2021

Biomark Res

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Deubiquitinases (DUBs) are enzymes that control the stability, interactions or localization of most cellular proteins by removing their ubiquitin modification. In recent years, some DUBs, such as USP7, USP9X and USP10, have been identified as promising therapeutic targets in hematological malignancies. Importantly, some potent inhibitors targeting the oncogenic DUBs have been developed, showing promising inhibitory efficacy in preclinical models, and some have even undergone clinical trials. Different DUBs perform distinct function in diverse hematological malignancies, such as oncogenic, tumor suppressor or context-dependent effects. Therefore, exploring the biological roles of DUBs and their downstream effectors will provide new insights and therapeutic targets for the occurrence and development of hematological malignancies. We summarize the DUBs involved in different categories of hematological malignancies including leukemia, multiple myeloma and lymphoma. We also present the recent development of DUB inhibitors and their applications in hematological malignancies. Together, we demonstrate DUBs as potential therapeutic drug targets in hematological malignancies.

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Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

Cited by 43 publications

References 66 publications

Role of Ubiquitin-Specific Peptidase 47 in Cancers and Other Diseases

Role of Ubiquitin-Specific Peptidase 47 in Cancers and Other Diseases

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Deubiquitinases in hematological malignancies

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