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Updated: Jan 17, 2026
Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
Published on: June 6, 2025
USP5 inhibition enables potential therapy for t(8;21) AML through ubiquitin-mediated AML1-ETO degradation in
Lan Ma1, Kun Zhang1, Zixuan Zhang1,2
1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, School of Life Sciences, Nankai University, Tianjin 300071, P. R. China.
Abstract:
The AML1-ETO (AE) fusion protein is a key target for treating t(8;21) acute myeloid leukemia (AML). In this investigation, we identified ubiquitin-specific protease 5 (USP5) as the deubiquitinating enzyme of AE. USP5 knockdown decreased AML cell growth and induced differentiation both in vitro and in vivo. In addition, we developed a high-throughput screening (HTS) method and identified a potent, selective USP5 inhibitor, WCY-8-67. This lead compound was identified as a selective USP5 inhibitor by targeting the ubiquitin-associated domain 2 (UBA2) region. It also induced aggregation and precipitation of the target protein, which led to USP5 dysfunction. WCY-8-67 exhibited excellent in vivo bioavailability and tolerability, and it effectively inhibited the growth of AML cells in animal models. In addition, in a patient-derived xenograft (PDX) model, this compound, when combined with 5-azacytidine (5-Aza), improved therapeutic effects. This study presents promising targeted therapeutic possibilities for the treatment of t(8;21) AML that require further study.
Insights
Researchers found that targeting ubiquitin-specific protease 5 (USP5) can treat acute myeloid leukemia (AML). A new inhibitor, WCY-8-67, effectively reduced AML cell growth and showed promise in preclinical models, including combination therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The AML1-ETO (AE) fusion protein is a critical driver in t(8;21) acute myeloid leukemia (AML).
- Targeting AE or its regulatory enzymes is a potential therapeutic strategy for t(8;21) AML.
- Identifying specific enzymes involved in AE regulation is crucial for developing targeted therapies.
Purpose of the Study:
- To identify the deubiquitinating enzyme responsible for the stability of the AML1-ETO (AE) fusion protein.
- To develop and characterize a novel inhibitor targeting this deubiquitinating enzyme for potential AML treatment.
- To evaluate the efficacy of the identified inhibitor in preclinical AML models.
Main Methods:
- Ubiquitin-specific protease 5 (USP5) was identified as the deubiquitinating enzyme for AE.
- USP5 knockdown was performed to assess its effect on AML cell growth and differentiation.
- A high-throughput screening (HTS) assay was developed to identify USP5 inhibitors.
- A selective USP5 inhibitor, WCY-8-67, targeting the UBA2 region, was identified and characterized.
- In vitro and in vivo studies, including patient-derived xenograft (PDX) models, were conducted to evaluate WCY-8-67 efficacy.
Main Results:
- USP5 deubiquitinates the AE fusion protein.
- Knockdown of USP5 inhibited AML cell proliferation and induced differentiation.
- WCY-8-67 was identified as a potent and selective USP5 inhibitor that causes protein aggregation and dysfunction.
- WCY-8-67 demonstrated good in vivo bioavailability and tolerability, inhibiting AML growth in animal models.
- Combination therapy with WCY-8-67 and 5-azacytidine showed enhanced therapeutic effects in a PDX model.
Conclusions:
- USP5 is a key regulator of the AE oncoprotein in t(8;21) AML.
- The novel USP5 inhibitor WCY-8-67 represents a promising targeted therapeutic agent for t(8;21) AML.
- WCY-8-67, particularly in combination therapy, warrants further investigation for clinical application in AML treatment.
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