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A higher-order configuration of the heterodimeric DOT1L–AF10 coiled-coil domains potentiates their leukemogenenic activity

Significance The leukemogenic function of the MLL1–AF10 fusion protein is caused by aberrant recruitment of histone methyltransferase DOT1L to MLL1-regulated genes, yet a precise picture of their interaction remains elusive. Here, we find that AF10 and DOT1L forms a tight binary complex via packing of the leucine zipper helix of AF10 and the first coiled-coil helix of DOT1L. Surprisingly, 4 DOT1L–AF10 heterodimers form a tetramer of heterodimers. We show that the hetero-octamer exists in solution, and the oligomeric form of the AF10–DOT1L complex is crucial for the leukemogenic activity of MLL1–AF10. This discovery reveals the molecular basis of the pathogenic function by MLL1–AF10 and may facilitate the development of more effective strategy against MLL1–AF10-mediated leukemia. Chromosomal translocations of MLL1 (Mixed Lineage Leukemia 1) yield oncogenic chimeric proteins containing the N-terminal portion of MLL1 fused with distinct partners. The MLL1–AF10 fusion causes leukemia through recruiting the H3K79 histone methyltransferase DOT1L via AF10’s octapeptide and leucine zipper (OM-LZ) motifs. Yet, the precise interaction sites in DOT1L, detailed interaction modes between AF10 and DOT1L, and the functional configuration of MLL1–AF10 in leukeomogenesis remain unknown. Through a combined approach of structural and functional analyses, we found that the LZ domain of AF10 interacts with the coiled-coil domains of DOT1L through a conserved binding mode and discovered that the C-terminal end of the LZ domain and the OM domain of AF10 mediate the formation of a DOT1L–AF10 octamer via tetramerization of the binary complex. We reveal that the oligomerization ability of the DOT1L–AF10 complex is essential for MLL1–AF10’s leukemogenic function. These findings provide insights into the molecular basis of pathogenesis by MLL1 rearrangements.