Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through...

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• Acute myeloid leukaemia (AML) is characterized by a complex bone marrow immune microenvironment.
• Understanding immune cell dynamics is crucial for deciphering AML development and drug resistance.
• E3 ubiquitin ligase-related genes play a role in leukaemogenesis and treatment response.

Purpose of the Study:

• To investigate the immune microenvironment in AML patients with and without resistance to chemotherapy.
• To explore the role of T cell subpopulations and E3 ubiquitin ligases in AML progression and drug resistance.
• To identify mechanisms underlying resistance to cytarabine (Ara-C) in AML.

Main Methods:

• Integration of multiple single-cell RNA sequencing datasets from AML patients.
• Comparative analysis of immune cell composition and interactions in AML remission (AML-CR) versus non-remission (AML-NR) cohorts.
• In vivo and in vitro experiments to assess the functional role of RNF149.

Main Results:

• Distinct immune microenvironments and altered T cell ratios (CD4+, Treg, CD8+) were observed in AML-NR compared to AML-CR.
• The E3 ubiquitin ligase RNF149 was found to accelerate AML progression and modify the immune milieu.
• RNF149 induces CD8+ T cell dysfunction, promotes transformation to exhausted T cells (T_Exh), enhances drug-resistant cell proliferation, and inhibits apoptosis, leading to Ara-C resistance.

Conclusions:

• The immune microenvironments of AML-CR and AML-NR patients differ significantly.
• RNF149 exhibits tumorigenic functions in AML, contributing to disease progression and therapeutic resistance.
• RNF149 represents a potential prognostic biomarker and a therapeutic target for overcoming AML drug resistance.