Forces of Attraction

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A mutation causing two genes to fuse kick starts a process that results in blood cancer.
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NMR spectrometry used by the researchers in this study relies on incredibly strong magnets. The magnets are so strong that a perimeter must be drawn several feet from the NMR machine in which magnetic materials, such as certain metals, medical implants and pacemakers, are not permitted.

In the classic 1980s film Fatal Attraction, a man and a woman enter into a relationship that heads down a dark path. It is safe to say that they were better off apart.

Similarly, genetic mutations can sometimes cause two separate genes to fuse together. Once fused, these genes can create abnormal molecules, known as fusion proteins, with similarly harmful consequences.

One such genetic fusion, known as MLL-AF6, is found in people that often develop leukemia, a cancer of the blood; however, it is not known exactly how the resulting fusion protein promotes the disease.

To address this gap in knowledge, Dr. Mitsu Ikura (PM Senior Scientist) and Dr. Matthew Smith (a former research associate in Dr. Ikura’s lab and now a faculty member of Université de Montréal’s Institute for Research in Immunology and Cancer) used NMR spectroscopy—a technology that uses powerful magnets to study the properties of molecules—to determine how the structure of the MLL-AF6 fusion protein influences its function.

Their research team found that the MLL-AF6 fusion protein had an abnormal structure: portions of the MLL and AF6 proteins that were normally hidden deep within the molecules were exposed on the surface of the MLL-AF6 fusion. These portions, known as hydrophobic regions, are attracted to other hydrophobic regions and cause one MLL-AF6 fusion protein to stick to another MLL-AF6 fusion protein—creating a pair.

The researchers found that the ability of one MLL-AF6 protein to pair with another was key to its role in promoting cancer: pairs of MLL-AF6 fusion proteins bound to DNA and turned on a set of genes that promote leukemia. When the researchers prevented the fusion proteins from pairing in an experimental model, the development of disease was halted.  

“Our study takes us one step closer to revealing how cancer develops: our results identify the exact ways that gene fusions can change the shape and function of proteins in the cell,” explains Dr. Ikura. “We’ve revealed two promising strategies—targeting the abnormally exposed portions of the protein and preventing the proteins from pairing—to develop new anti-leukemia drugs."

This work was supported by the Cancer Research Society; the Canadian Cancer Society Research Institute; the Canadian Institutes of Health Research; the Leukemia & Lymphoma Society Canada; the Natural Sciences and Engineering Research Council of Canada; Ministère de l'Éducation et de l'Enseignement supérieur Québec; Fonds de recherche du Québec - Nature et technologies; Fonds de recherche du Québec- Santé; Deutsche Forschungsgemeinschaft; the Canada Foundation for Innovation; and The Princess Margaret Cancer Foundation. M Ikura is a Tier 1 Canada Research Chair in Cancer Structural Biology, AC Gingras is a Tier 1 Canada Research Chair in Functional Proteomics and MJ Smith is a Tier 2 Canada Research Chair in Cancer Signalling and Structural Biology.

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. Evolution of AF6-RAS association and its implications in mixed-lineage leukemia. Nat Commun. 2017 Oct 23. doi: 10.1038/s41467-017-01326-5.