DNA methylation modulation by Azacytidine can restore T cell function and exhaustion in AML.

ABSTRACT: AML is an aggressive malignancy of the blood and bone marrow associated with poor clinical outcome. Chemotherapy remains the standard of treatment, yet relapse is common, highlighting the need to find alternative therapies. T cell dysfunction and exhaustion are prominent in AML and represent a key barrier to effective immunotherapy. DNA methylation is a major driver of T cell exhaustion and inhibition of de novo methylation can restore T cell function in other disease contexts. Here we investigated the impact of Azacytidine (Aza), an FDA approved hypomethylating agent, on T cell exhaustion in AML. Using a spontaneous AML mouse model and AML patient samples, we find that Aza treatment modulates T cell function. In vivo Aza treatment decreased tumor burden and reshaped CD8+ T cells states, increasing memory subsets and decreasing regulatory T cells (Tregs) frequency in mice. Functionally, Aza treatment overcomes the impaired proliferation in both CD4 and CD8+ T cells in our model. DNA methylation sequencing reveled hypomethylation and increased expression of stem like precursor gene TCF7 and E2F2, a regulator of cell cycle progression and proliferation. Similar changes in phenotypes are observed in cultures of AML patient samples with Aza. Collectively, we show that Aza remodels epigenetic and functional states in AML and has the potential to reverse T cell exhaustion, with enhanced memory and proliferation capacity. Our work provides a mechanistic framework supporting the rationale of combining hypomethylating agents with T cell based immunotherapies for this lethal disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE328721 | GEO | 2026/04/22

REPOSITORIES: GEO