01:44am Saturday 25 November 2017

Using epigenetics to fight blood cancers

Cell biology has an ever-growing cast of molecules that regulate how cells perform. In many cases, proteins bind to other proteins to change their trajectory and alter cellular function. These binding interactions are incredibly important to understand. In particular, researchers are trying to figure out why changes in the interactions of proteins can cause cancer.

Recently, Stephen D. Nimer, M.D., director of Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, was co-senior author on a paper, published in the journal PNAS, that describes how the protein DPF2 regulates blood production. DPF2 helps determine whether blood cells stay immature or mature into various cell types. High levels of DPF2 are seen in patients with acute myelogenous leukemia (AML), an aggressive type of blood cancer.

“We wanted to understand the mechanisms that drive AML and other blood cancers,” said Nimer. “Because DPF2 plays such an essential role in regulating how cells mature or differentiate, understanding how it functions is a real priority.”

Sylvester researchers teamed up with colleagues at Caltech, who used a technique called X-ray crystallography to take 3-D images of DPF2. Together, they were able to determine the protein’s molecular structure and understand how DPF2 binds to histones, the proteins that package DNA. Crystallography is extremely useful to figure out how different molecules attach to each other. In fact, it was the X-ray images created by Rosalind Franklin that allowed Watson and Crick to decipher DNA’s structure.

Histones perform an important job on a number of levels. First, there’s a lot of DNA, around six feet in each cell. It has to be packaged tightly to fit in, but it also needs to be selectively loosened so appropriate genes can express themselves. The study of DNA and histones is called epigenetics and since 2012 Sylvester has built an ever-expanding cancer epigenetics program.

Examining DPF2’s crystal structure told the researchers a lot about how the protein influences DNA structure and gene expression. Specifically, they focused on a part of the protein called the PHD fingers and showed how they bind to histones.

While DPF2 is found in cells all over the body, this study focused on its important role in bone marrow cells, where it prevents them from differentiating.

“Unfortunately, when DPF2 is very active, it prevents myeloid differentiation, which is needed for normal blood formation,” said Nimer. “That is the case in AML and poses risks for other cancers.”

Learning more about how DPF2 regulates DNA structure, and influences differentiation, could be good news for AML patients. Molecular switches that drive cancer cell growth could be turned off once we understand how things work in the cell.

“We’ve seen some encouraging results using epigenetic drugs to treat cancer,” said Nimer. “We hope to take a similar approach targeting DPF2. This could give us another tool against cancers like AML.”

Miller School of Medicine

 


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