Immune evasion mechanisms in paediatric B-cell acute lymphoblastic leukemia (B-ALL) hinder the efficacy of immunotherapies. Epitranscriptomic regulators such as m6A readers may modulate immune landscapes in B-ALL, but their roles remain poorly defined. Transcriptomic analysis of paediatric B-ALL samples highlighted YTHDF1 and ALYREF as co-upregulated candidates. Functional studies in YTHDF1-silenced B-ALL cells assessed ALYREF mRNA stability, PD-L1 expression, and migratory capacity. NSG xenograft models were used to investigate immune cell infiltration profiles. YTHDF1 enhanced ALYREF mRNA stability via binding to m6A-modified transcripts, promoting downstream PD-L1 expression. Knockdown of YTHDF1 led to significant reductions in ALYREF (60%) and PD-L1, accompanied by a 50% reduction in cell migration. Notably, CD8 + T cell infiltration in xenografts increased 2.5-fold, indicating improved tumor immunogenicity. The YTHDF1–ALYREF–PD-L1 axis represents a novel immune evasion mechanism in B-ALL. Therapeutic disruption of this pathway may restore T cell-mediated cytotoxicity and enhance the efficacy of existing immunotherapies.
Sang et al. (Tue,) studied this question.