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Tracking The Molecular Pathway To Mixed-lineage Leukemia

Date:
December 15, 2008
Source:
Whitehead Institute for Biomedical Research
Summary:
The MLL-AF4 fusion protein, which causes the blood cancer called mixed-lineage leukemia, binds to several genes responsible for early blood cell development. MLL-AF4 also alters the chromatin proteins associated with these genes, a state that is associated with cancer and leukemia progression. Patients with mixed-lineage leukemia have a very poor prognosis. Understanding the molecular pathway for how the MLL-AF4 protein interacts with genes may lead to future gene-targeted therapies.

Infants and adults with the blood cancer mixed-lineage leukemia (MLL) typically have a poor prognosis, and most infants die before their first birthdays. Although there are varying causes of MLL, most cases are caused by a fusion of two genes, the MLL and the AF4 genes.

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When the MLL gene is fused to the AF4 gene, a potent cancer-causing oncogene is created. Although researchers have known that the MLL-AF4 protein produced by this genetic fusion causes leukemia, they had not been able to determine precisely how this oncogene disrupted cells' normal protein production.

To pinpoint the oncogene's activities, Matthew Guenther, a postdoctoral researcher in Whitehead Member Richard Young's lab, used a technique called ChIP-seq (chromatin immunoprecipitation with DNA sequencing) to map where the MLL-AF4 protein interacts with a cell's genome. He 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 (the genes that initiate blood cell production).

It seems that when the MLL-AF4 protein interacts with these genes, it forces them into a hyperactive state, with disastrous consequences.

"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 Guenther.

Looking closer at the MLL-AF4 protein-bound genes, Guenther noticed that these genes display strange patterns of chromatin proteins. In the cell, DNA is wrapped around chromatin proteins for dual purposes: to safely package DNA for cell division and to control gene expression (epigenetics). 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.

Guenther's findings may take scientists one step closer to a treatment for this deadly disease.

"We think we've figured out a key piece of how this leukemia works," says Young. "If we understand the molecular pathway for how the MLL-AF4 protein interacts with genes, it gives us a set of new target genes that might be used for drug development."

Richard Young's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.


Story Source:

The above story is based on materials provided by Whitehead Institute for Biomedical Research. Note: Materials may be edited for content and length.


Journal Reference:

  1. Lee N. Lawton et al. Aberrant Chromatin at Genes Encoding Stem Cell Regulators in Human Mixed-lineage Leukemia. Genes and Development, December 15, 2008

Cite This Page:

Whitehead Institute for Biomedical Research. "Tracking The Molecular Pathway To Mixed-lineage Leukemia." ScienceDaily. ScienceDaily, 15 December 2008. <www.sciencedaily.com/releases/2008/12/081215184347.htm>.
Whitehead Institute for Biomedical Research. (2008, December 15). Tracking The Molecular Pathway To Mixed-lineage Leukemia. ScienceDaily. Retrieved November 24, 2014 from www.sciencedaily.com/releases/2008/12/081215184347.htm
Whitehead Institute for Biomedical Research. "Tracking The Molecular Pathway To Mixed-lineage Leukemia." ScienceDaily. www.sciencedaily.com/releases/2008/12/081215184347.htm (accessed November 24, 2014).

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