Multi-scale transcriptomics analysis reveals MHC suppression in MEF2D fusion positive B-cell acute lymphoblastic leukemia.

MEF2D gene related fusions, define a unique B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis. In this study, we performed single-cell RNA sequencing (scRNA-seq) on three MEF2D fusion cases and collected transcriptomic data of 81 BCP-ALL cases with MEF2D fusions from public datasets. By comparing scRNA-seq profiles with those of normal bone marrow cells and other BCP-ALL subtypes, we identified a characteristic pre-B cell developmental arrest specific to the MEF2D subtype. Single-cell analyses indicated a pronounced reduction of major histocompatibility complex (MHC) expression, suggesting a potential mechanism of immune evasion, which could be further corroborated by cell-cell communication analysis. Bulk RNA-seq data verified the downregulation of MHC molecules in MEF2D subtype, which was consistent with the downregulation of CIITA, the transactivator of MHC molecules. Knockdown of the MEF2D-HNRNPUL1 fusion in the Kasumi-7 cell line led to the upregulation of MHC molecules. ChIP-seq data of the Kasumi-7 cell line showed that the MEF2D::HNRNPUL1 fusion protein directly bound to the region next to an intronic enhancer sequence of CIITA, indicating a MEF2D-CIITA-MHC potential pathogenic mechanism. This study offers a comprehensive analysis of MEF2D-fusion cases, detailing the fusion features and functional alterations, thus providing insights for future investigations.