A Bacterial Mutation May Help Improve Leukemia Treatment

Scientists were able to alter an enzyme that is already used to treat the disease.

11/16/2017 11:01 EST | Updated 11/16/2017 11:25 EST
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Each year, an estimated 6,000-plus Canadians are faced with a rather dire health diagnosis. They have leukemia, or cancer of the blood. While treatments and options for care exist, the disease still leads to an estimated 2,900 deaths a year.

The trouble with treating leukemia is the need for a systemic approach. Normally, therapy involves a single area of the body, such as the lungs or the brain. But treatments for leukemia need to travel throughout the body. As a result, the first line of defense is chemotherapy.

One trusted option for treatment particularly in children is a chemical known as L-asparaginase, shortened to ASPase. It's not a drug but rather a naturally produced biological enzyme. How it works is quite fascinating. The molecule enters a cancerous cell and convinces it to commit suicide. The effect is so useful, ASPases have about a 60-per-cent success rate in a certain type of leukemia known as acute lymphocytic leukemia, or ALL. That's why for the last five decades, this form of treatment has been regarded as one of the better ways to fight the illness.

However, the treatment is not perfect. Researchers have known for some time that cancer, and to some extent immune cells, react to this enzyme and do all they can to break it down quickly. This leads to a battle in which more enzyme may be needed to fight. Unfortunately, this could put the patient at risk for toxicity. If the situation becomes too risky, the treatment may end up being shelved for the sake of the patient.

Though much more work needs to be done to determine if it can be used in humans, for the thousands of people suffering from leukemia, this study brings hope for the future.

For years, researchers have looked at ways of improving the lifespan and effect of ASPases in the laboratory but discoveries have been few and far between. Yet there may now be a path forward. As an international group of scientists have found, a small modification in the enzyme may offer hope for improved treatment.

The group focused on one of the main manufacturers of the enzyme, the bacterium Escherichia coli. While better known as a pathogen, this species can be used for good, including the production of drugs such as insulin and various pharmaceuticals. The team hoped to find a way to genetically engineer the enzyme such that it could resist the cancer cell's defenses.

The team examined all aspects of the protein but soon found their attention directed at a small region known as a flexible loop. As the name implies, this region of the enzyme floats around in the open space and is vulnerable to breakage. The group wondered if genetically modifying this region would somehow result in a mutant version that could be effective in use and resist the cancer cell's defenses.

The team came across one mutation that appeared to work. Known simply as N24S, the new version of the enzyme had a longer lifespan in storage and was resistant to the effects of heat. When it was compared to regular ASPases, the mutant was comparable in its ability to kill leukemia cells.

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But this was just the groundwork for the real test. The team still needed to find out if N24S could resist the attacks from cancer and immune cells. When they did the experiment in the lab, they were pleased with the results. In the case of the normal enzyme, only about 15 per cent of the cancer cells were killed. But when N24S was used, that number rose to 80 per cent.

The team also hoped to see the same response to attack from immunity. Computer analysis revealed the mutation would be less likely to trigger an immune response. At least in principle, N24S would be safer to use, although this would have to be tested in more natural environments to be sure.

Taking a closer look as to why this slight mutation led to such a dramatic change in activity, the team realized they had changed the way the flexible loop looked to the defense forces. It was more rigid and less likely to be broken apart. In the same manner as antibiotic resistance, the N24S version was no longer vulnerable to attack.

The discovery of N24S highlights once again how minor changes in proteins can have a dramatic effect on function. Normally, this is considered troublesome, but in this case, the alteration produced a benefit. Though much more work needs to be done to determine if it can be used in humans, for the many people suffering from leukemia, this study brings hope for the future. Using N24S, we may one day be able to treat leukemia more safely and effectively.

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