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

Matthew J. Smith (), Elizabeth Ottoni, Noboru Ishiyama, Marilyn Goudreault, André Haman, Claus Meyer, Monika Tucholska, Genevieve Gasmi-Seabrook, Serena Menezes, Rob C. Laister, Mark D. Minden, Rolf Marschalek, Anne-Claude Gingras, Trang Hoang and Mitsuhiko Ikura ()
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Matthew J. Smith: Université de Montréal
Elizabeth Ottoni: Université de Montréal
Noboru Ishiyama: Princess Margaret Cancer Centre
Marilyn Goudreault: Université de Montréal
André Haman: Université de Montréal
Claus Meyer: Goethe-University of Frankfurt
Monika Tucholska: Mount Sinai Hospital
Genevieve Gasmi-Seabrook: Princess Margaret Cancer Centre
Serena Menezes: Princess Margaret Cancer Centre
Rob C. Laister: Princess Margaret Cancer Centre
Mark D. Minden: Princess Margaret Cancer Centre
Rolf Marschalek: Goethe-University of Frankfurt
Anne-Claude Gingras: Mount Sinai Hospital
Trang Hoang: Université de Montréal
Mitsuhiko Ikura: Princess Margaret Cancer Centre

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01326-5

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