MECOM promotes leukemia progression and inhibits mast cell differentiation through functional competition with GATA2 (CordBlood_RNA-seq)

Germline mutations clustered in the C-terminal zinc finger domain (ZFD) of MECOM are known to cause MECOM-associated syndromes, involving bone marrow failure and skeletal anomalies. However, the molecular consequences of these mutations and the precise downstream mechanisms of MECOM remain elusive.

Here, we demonstrate that the C-terminal ZFD serves as the dominant DNA-binding module of MECOM, and that disease-associated mutations abrogate its DNA-binding capacity. Mechanistically, we reveal that MECOM functionally antagonizes GATA2 via C-terminal ZFD-mediated DNA binding and recruitment of the corepressor CtBP. This repression promotes myeloid leukemogenesis while suppressing mast cell differentiation.