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

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.

Authors:
ORCiD logo; ; ; ; ; ; ; ; ; ; ; ORCiD logo; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGN
OSTI Identifier:
1409101
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Communications; Journal Volume: 8; Journal Issue: 1
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

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, and Ikura, Mitsuhiko. Evolution of AF6-RAS association and its implications in mixed-lineage leukemia. United States: N. p., 2017. Web. doi:10.1038/s41467-017-01326-5.
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. Evolution of AF6-RAS association and its implications in mixed-lineage leukemia. United States. doi:10.1038/s41467-017-01326-5.
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, and Ikura, Mitsuhiko. Mon . "Evolution of AF6-RAS association and its implications in mixed-lineage leukemia". United States. doi:10.1038/s41467-017-01326-5.
@article{osti_1409101,
title = {Evolution of AF6-RAS association and its implications in mixed-lineage leukemia},
author = {Smith, Matthew J. and Ottoni, Elizabeth and Ishiyama, Noboru and Goudreault, Marilyn and Haman, André and Meyer, Claus and Tucholska, Monika and Gasmi-Seabrook, Genevieve and Menezes, Serena and Laister, Rob C. and Minden, Mark D. and Marschalek, Rolf and Gingras, Anne-Claude and Hoang, Trang and Ikura, Mitsuhiko},
abstractNote = {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.},
doi = {10.1038/s41467-017-01326-5},
journal = {Nature Communications},
number = 1,
volume = 8,
place = {United States},
year = {Mon Oct 23 00:00:00 EDT 2017},
month = {Mon Oct 23 00:00:00 EDT 2017}
}