Keeping Cancer in Its Place – Key Protein Identified

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Sylvester researchers show the p300 protein can prevent myelodysplastic syndromes from becoming full-blown acute leukemia.

Stephen Nimer, M.D., director of the Sylvester Comprehensive Cancer Center.

Researchers with Sylvester Comprehensive Cancer Center at the University of Miami’s Miller School of Medicine have used mouse models to determine that promoting the activity of the p300 protein helps prevent myelodysplastic syndrome (MDS) from evolving into acute myeloid leukemia (AML). These findings could ultimately translate into new treatments that stall MDS progression. The study was published in the journal JCI Insight. 

“Many MDS patients will progress to AML, which is more deadly, but we do not fully understand the mechanisms involved,” said Stephen Nimer, M.D., senior author on the paper and Director of Sylvester Comprehensive Cancer Center. “Now that we have identified an important role for p300 in preventing MDS progression, we can potentially manipulate its activity therapeutically.”

The bone marrow has difficulty producing blood cells in MDS patients leading to shortages in red blood cells, which can generate anemia, white blood cells, which impairs the body’s defense against infections, and platelets, which leads to a significant bleeding tendency.

In the study, the researchers found deleting or inhibiting p300 impairs the epigenetic machinery that controls gene expression triggering the development of AML. Specifically, p300 regulates chromatin – the three-dimensional combination of proteins and DNA that helps manage which genes are turned on or off in the cell.

Concepcion Martinez Caja
Concepcion Martinez Caja

The study showed, in both cell and animal models, that inhibiting p300 generates chromatin modifications and multiple gene expression changes, including boosting the Myb and Hox B proteins, which have been implicated in AML progression.

“We use inhibitors as a tool to interrogate how the system works,” said co-author and director of the research laboratory, Concepcion Martinez Caja. “When we treat cells with the inhibitor, we can correlate the changes in gene expression with the transition from MDS to AML.”

These findings indicated that losing p300 activity played a critical role in disease progression, increasing cell proliferation and giving the cells greater capacity to become increasingly malignant.

Gloria Mas Martin, Ph.D.
Gloria Mas Martin, Ph.D.

“We found that, for the common MDS mutations we tested, losing p300 accelerates disease progression making it extremely aggressive,” said associate scientist Gloria Mas Martin, Ph.D., who was co-first author on the paper. “And though Myb was known to interact with p300, its role in the transition from myelodysplastic syndrome to acute myeloid leukemia had not been reported before.”

Most importantly, activating p300 had the opposite effect, reducing expression of Myb and other cancer-associated proteins and preventing MDS from evolving into AML.

“If we activate p300 we can impede the reprogramming that transforms cells from myelodysplastic syndrome to acute leukemia,” said Dr. Mas Martin. “With further exploration, this could be quite useful therapeutically.”

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