The research team of Professor Matthew J. Smith, a young Principal Investigator at the IRIC who specializes in signalling and structural biology, recently elucidated a molecular mechanism underlying certain leukemias. Their recent publication in the journal Nature Communications, in collaboration with research teams in Toronto and the team of Trang Hoang at the IRIC, explains how a specific chromosomal rearrangement fusing the human MLL gene with the AF6 gene gives rise to a fusion protein with new, oncogenic activity in cells. MLL-AF6 fusions in patients are responsible for highly acute leukemias in both children and adults, with no available therapies. The research teams demonstrate that this genetic translocation event truncates a small region of the AF6 protein, exposing several hydrophobic residues that nucleate formation of a protein dimer: a complex of two MLL-AF6 fusion proteins. Resultant MLL dimer proteins function atypically, by promoting the expression of several genes that directly initiate cancer. The researchers also show that in a mouse model, inhibiting dimerization of MLL-AF6 fusion proteins completely prevents the development of leukemia. Furthermore, it appears that this molecular mechanism is conserved in fusions of MLL with other gene partners, suggesting that inhibiting dimerization could represent a valid therapeutic approach for numerous aggressive leukemias.

Structural model of two AF6 RA1 domains in dimer formation, responsible for activation of gene expression in MLL-AF6 fusions


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Study cited

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

Smith MJ, Ottoni E, Ishiyama N, Goudreault M, Haman A, Meyer C, Tucholska M, Gasmi-Seabrook G, Menezes S, Laister RC, Minden MD, Marschalek R, Gingras AC, Hoang T, Ikura M

Nat Commun 2017-10-23;8(1):1099.