MEF2D (myocyte enhancer factor 2D) is a transcription factor that plays critical roles in both normal development and leukemogenesis. In acute lymphoblastic leukemia (ALL), MEF2D undergoes chr1 rearrangements with multiple fusion partners including BCL9, CSF1R, DAZAP1, HNRNPUL1, SS18, and FOXJ2 1. These MEF2D rearrangements occur in approximately 5.3% of B-ALL cases lacking other recurring alterations and define a distinct molecular subtype with characteristic features 1. MEF2D-rearranged ALL patients typically present at older ages, have distinct immunophenotypes, and demonstrate poor clinical outcomes 1 2. The fusion proteins result in enhanced MEF2D transcriptional activity and lymphoid transformation, with activation of HDAC9 expression making these leukemias sensitive to histone deacetylase inhibitor treatment 1. Single-cell RNA sequencing studies reveal that MEF2D-rearranged B-ALL shows enrichment of pre-B cell developmental states 3. Beyond B-ALL, MEF2D also contributes to acute myeloid leukemia progression through a positive feedback loop with IRF8 and regulation of the MEF2D-CEBPE transcriptional axis 4. These findings establish MEF2D rearrangements as defining a high-risk ALL subtype requiring specialized therapeutic approaches.