Structural and functional analysis of the DOT1L–AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis

Abstract

The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A (<i>HOXA</i>) gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10^OM-LZ and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation. We further show that zinc stabilizes the DOT1L-AF10 complex and may be involved in the regulation of the <i>HOXA</i> gene expression. Our studies may also pave the way for the rational design of therapeutic drugs against <i>MLL</i>-rearranged leukemia.