Evolution of AF6-RAS association and its implications in mixed-lineage leukemia

• Published in: Nature communications Vol. 8; no. 1; pp. 1099 - 13
• Main Authors: Smith, Matthew J, Ottoni, Elizabeth, Ishiyama, Noboru, Goudreault, Marilyn, Haman, André, Meyer, Claus, Tucholska, Monika, Gasmi-Seabrook, Genevieve, Menezes, Serena, Laister, Rob C, Minden, Mark D, Marschalek, Rolf, Gingras, Anne-Claude, Hoang, Trang, Ikura, Mitsuhiko
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.10.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: 60 APPLIED LIFE SCIENCES; Amino Acid Sequence; BASIC BIOLOGICAL SCIENCES; Chromosome rearrangements; Chromosome translocations; Dimerization; Dimers; Evolution, Molecular; Gene expression; Humans; Hydrophobicity; Kinesin - chemistry; Kinesin - genetics; Kinesin - metabolism; Leukemia; Leukemia - enzymology; Leukemia - genetics; Leukemogenesis; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; MLL protein; Models, Molecular; Modulators; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Myosins - chemistry; Myosins - genetics; Myosins - metabolism; Oligomerization; Oncogene Protein p21(ras) - chemistry; Oncogene Protein p21(ras) - genetics; Oncogene Protein p21(ras) - metabolism; Protein Binding; Protein Domains; Protein structure; Protein transport; Proteins; Structure-function relationships; Translocation; Translocation, Genetic; Tumorigenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01326-5

Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization. We provide evidence that oligomerization is the dominant mechanism driving oncogenesis from rare MLL translocation partners and employ our mechanistic understanding of MLL-AF6 to examine how dimers induce leukemia. Proteomic data resolve association of dimerized MLL with gene expression modulators, and inhibiting dimerization disrupts formation of these complexes while completely abrogating leukemogenesis in mice. Oncogenic gene translocations are thus selected under pressure from protein structure/function, underscoring the complex nature of chromosomal rearrangements.