RUNX1 Is a Key Target in t(4;11) Leukemias that Contributes to Gene Activation through an AF4-MLL Complex Interaction

SummaryThe Mixed Lineage Leukemia (MLL) protein is an important epigenetic regulator required for the maintenance of gene activation during development. MLL chromosomal translocations produce novel fusion proteins that cause aggressive leukemias in humans. Individual MLL fusion proteins have distinct leukemic phenotypes even when expressed in the same cell type, but how this distinction is delineated on a molecular level is poorly understood. Here, we highlight a unique molecular mechanism whereby the RUNX1 gene is directly activated by MLL-AF4 and the RUNX1 protein interacts with the product of the reciprocal AF4-MLL translocation. These results support a mechanism of transformation whereby two oncogenic fusion proteins cooperate by activating a target gene and then modulating the function of its downstream product.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A common set of target genes directly regulated by MLL-AF4 is identified ► RUNX1 is a target gene that is specifically upregulated in t(4;11) patients ► MLL-AF4 controls RUNX1 gene expression by stabilizing ENL and AF9 binding ► RUNX1 cooperates with an AF4-MLL complex to activate gene targets