Researchers Claim Silencing a Protein may Prevent Leukemia

Blocking signals from a specific protein that activates cells in the immune system could help kill cells that cause leukemia, researchers at Penn State Hershey Cancer Institute have found.

The human immune system has a two-part strategy when dealing with infections. It generates antibodies that bind with bacteria and viruses to neutralize them.

For a short time, the immune system also produces large numbers of a type of white blood cell, cytotoxic T-cell that kills other infected cells.

Once the pathogens are eliminated, these killer T-cells quickly die on their own, save for a few that remain in case the same infection returns. But in rare cases, these cells fail to follow their scripted lifecycle.

"When these cells don't normally die, they expand gradually over time and start attacking the body itself. They can attack the joints to cause autoimmune diseases such as rheumatoid arthritis, and attack the bone marrow to cause leukaemia," said Thomas Loughran, M.D., lead author and director of Penn State Hershey Cancer Institute.

Loughran, professor of medicine, and his colleagues are trying to tease out the conditions that cause the abnormal expansion of T-cells and trigger a disease known as large granular lymphocyte leukemia.

Therefore, they constructed an intricate computer model illustrating the signaling network involved in the activation of the T-cells, as well as there programmed death.

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The network model strings together complex data of molecular pathways inside a cell involving hundreds of genes and proteins and tries to predict an outcome based on how the genes and proteins interact.

"The interactions among proteins make them turn ON or OFF or intermittently ON or OFF to get billions of possibilities with hundreds of proteins. By simulating the protein interactions and tracing the ON/OFF states of all those proteins at the same time, we can see whether the cells live or die," said Reka Albert, co-author and Penn State associate professor of physics and biology.

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Albert explains that the model could help researchers zero in on the exact location of the signaling abnormalities that are keeping T-cells from dying. Once that is known, specific genes or proteins could be targeted with drugs to get rid of the abnormality.

Sifting through the billions of possibilities projected by the model, the researchers have found two proteins - IL-15 and PDGF - that appear to be crucial in keeping the T-cells alive. While IL-15 is key to the survival and activation of T-cells, PDGF stimulates the growth of those cells.

"You need the presence of both these proteins to create conditions in which the cytotoxic T-cells can proliferate. That is a major point of the discovery," said Loughran.

The researchers have also discovered another signaling protein - NF?B - controlled by the two proteins, which protects cancer cells from dying if it is over expressed.

"NF?B controls a host of other proteins related to inflammation in the body and our model suggests that if we keep it in the OFF state, it is able to induce cell death in the T-cells. In other words, we can reverse the disease by setting this molecule OFF," said Albert.

When researchers blocked NF?B with drugs in cells from leukemia patients, they found a significant increase in mortality among the abnormal T-cells, suggesting that NF?B helps in the survival of leukemia cells.

"Basically when this protein is inhibited and not expressed anymore, the cells die. It validates our model," said Loughran.

The study was published in the Proceedings of the National Academy of Sciences.

Source-ANI
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