The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia

Area of Science:

• Epigenetics
• Molecular Biology
• Cancer Research

Background:

• The non-canonical PRC1.1 Polycomb complex's role in human leukemogenesis is not fully understood.
• Identifying key components and regulatory mechanisms of PRC1.1 is crucial for understanding its function in cancer.

Purpose of the Study:

• To elucidate the functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis.
• To identify integral components of PRC1.1 and their roles in regulating gene expression and cell proliferation.

Main Methods:

• Protein interactome analyses to identify PRC1.1 components.
• USP7 inhibition studies to assess PRC1.1 disassembly and chromatin binding.
• Assessment of histone modification levels (H2AK119ub, H3K27ac) and gene transcription.
• TRIM27 knockdown experiments to evaluate reciprocal requirements and drug sensitivity.
• In vitro proliferation assays in AML cells and in vivo leukemia xenograft models.

Main Results:

• USP7 and TRIM27 were identified as integral components of the PRC1.1 complex.
• USP7 inhibition led to PRC1.1 disassembly, loss of chromatin binding, and reduced H2AK119ub and H3K27ac levels.
• USP7 inhibition diminished transcription of PRC1.1-controlled genes and impaired AML cell proliferation.
• TRIM27 knockdown partially rescued sensitivity to USP7 inhibitors.
• USP7 inhibitors delayed leukemia progression in vivo.

Conclusions:

• USP7 and TRIM27 are essential for PRC1.1 integrity and function in leukemogenesis.
• USP7 inhibition disrupts PRC1.1, impacting epigenetic marks and gene expression, offering a potential therapeutic strategy for AML.
• USP7 inhibition demonstrates efficacy against AML cells both in vitro and in vivo, independent of the USP7-MDM2-TP53 axis.