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

The composition of the bone marrow immune microenvironment in patients with acute myeloid leukaemia (AML) was analysed by single-cell sequencing and the evolutionary role of different subpopulations of T cells in the development of AML and in driving drug resistance was explored in conjunction with E3 ubiquitin ligase-related genes.

To elucidate the mechanisms underlying AML-NR and Ara-C resistance, we analyzed the bone marrow immune microenvironment of AML patients by integrating multiple single-cell RNA sequencing datasets. When compared to the AML disease remission (AML-CR) cohort, AML-NR displayed distinct cellular interactions and alterations in the ratios of CD4⁺T, Treg, and CD8⁺T cell populations.

Our findings indicate that the E3 ubiquitin ligase RNF149 accelerates AML progression, modifies the AML immune milieu, triggers CD8⁺T cell dysfunction, and influences the transformation of CD8⁺ Navie.T cells to CD8⁺T_Exh, culminating in diminished AML responsiveness to chemotherapeutic agents. Experiments both in vivo and in vitro revealed RNF149's role in enhancing AML drug-resistant cell line proliferation and in apoptotic inhibition, fostering resistance to Ara-C.

In essence, the immune microenvironments of AML-CR and AML-NR diverge considerably, spotlighting RNF149's tumorigenic function in AML and cementing its status as a potential prognostic indicator and innovative therapeutic avenue for countering AML resistance.