MLL-AF4 was found to bind to 169 genes, forcing them into a hyperactive state, according to a Genes and Development article.

Investigators at the Whitehead Institute for Biomedical Research have pinpointed how the known oncogene for mixed-lineage leukemia (MLL), MLL-AF4, upsets cells’ natural protein production leading to leukemia.

Using the ChIP-seq technique, scientists mapped where the MLL-AF4 protein interacts with a cell’s genome. They found that in cancer cells the MLL-AF4 protein binds to at least 169 genes, many of which are overexpressed in leukemia cells and encode hematopoietic stem cell regulators that initiate blood cell production.

“The MLL-AF4 fusion protein is somehow targeted to a set of genes that essentially hijacks the blood stem cell machinery and makes that cell become cancerous, basically a younger-looking cell that is dividing much more than it should,” says Matthew Guenther, a postdoctoral researcher at the Whitehead Institute. 

On closer inspection of the MLL-AF4 protein-bound genes, the team also noticed that they display strange patterns of chromatin proteins, which normally safely packages DNA for cell division and controls gene expression. Changes in chromatin structures can affect normal gene expression, and other studies have linked chromatin misregulation to cancer and to leukemia disease progression. In MLL patients, it seems the MLL-AF4 protein alters the normal chromatin state of the hematopoietic stem cell regulators.

The paper can be found in the December 15 edition of Genes and Development.

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