Single-cell transcriptome profiling of m6A regulator-mediated methylation modification patterns in elderly AML patients

Abstract

Millions of people worldwide die of acute myeloid leukaemia (AML) each year. Although N6-methyladenosine (m⁶A) modification has been reported to regulate the pathogenicity of AML, the mechanism by which it induces the dysfunctional differentiation of haemocytes in elderly AML patients remains unclear. In this study, we illustrated the underlying mechanisms of the m⁶A landscape and specific mechanisms of m⁶A regulators in haemocytes of elderly patients with AML. Notably, FTO was upregulated in haematopoietic stem cells (HSCs), Myeloids and TCells and inhibited the differentiation of these cells through the WNT pathway. Additionally, upregulation of YTHDF2 expression in Erythrocytes induced the negative regulation of differentiation through oxidative phosphorylation, leading to leukocyte activation. Moreover, IGF2BP2 was markedly upregulated in Myeloids, contributing to a dysfunctional chromosomal region and dysregulated oxidative phosphorylation. m⁶A regulators induced aberrant cell-cell communication in haemocytes and mediated ligand-receptor interactions across diverse cell types by activating the HMGB1-mediated pathway, which promotes AML progression. Furthermore, a THP-1 cell model was used to verify the m⁶A regulator profile; in vitro infection of THP-1 cells with the short hairpin RNA (sh)-FTO blocked cell proliferation and migration while inducing cell cycle arrest and apoptosis. Overall, these results indicated that the upregulation of m⁶A regulators in HSCs, Erythrocytes, Myeloids, and TCells may induce malignant differentiation in patients with AML. Our research offers new perspectives on the pathogenesis and therapeutic targets of elderly AML.