Judging Cell Death Readiness

Acute myeloid leukemia cells primed to die are more responsive to chemotherapy

(RxWiki News) For some cancers, it takes trial and error to learn which treatments will work, and which will be best for the individual. A new tool may give people with a form of leukemia a better way to predict which treatments are effective.

A new tool being tested with acute myeloid leukemia (AML) appears effective in determining how ready and willing cancer cells are to die. The farther along cells are to self-destructing, the more responsive they will be to chemotherapy.

The method may one day help to select the right treatments for AML patients.

"Ask which tests are best for you."

Researchers at Dana-Farber Cancer Institute, were led by Anthony Letai, MD, PhD, assistant professor of medicine at Harvard Medical School and senior author of the paper.

"You don't want to give chemotherapy unless you know whether it will benefit,” Dr. Letai said. “Now we can predict who will benefit from it and who won't -- and should receive an alternative treatment."

What the test does is judge how far along the AML cells are to programmed cell death, a natural process called apoptosis. The more the cells are “primed to die,” the better the outlook for the patient, according to the study authors.

Cells that are farther along are more responsive to chemotherapy, while those that aren’t so ready to die may portend the need for more aggressive therapy such as a bone marrow transplant.

This new investigational method uses a technique called "BH3 profiling" to measure the readiness of mitochondria (cell powerhouses) to expel chemicals that cause cells to commit suicide.

What the scientists referred to as “death molecules” are at the heart of the self-destruction process. These assassins are on the lookout for and slay severely damaged and unnecessary cells.

The study's coined the term "mitochondrial priming" to describe self-destruction readiness.

The test exposes leukemia cells to BH3, which behave like the death molecules. If the mitochondria start to crumble, then the cells are more responsive to chemotherapy. If the mitochondria doesn’t flinch in the presence of the BH3, then more aggressive therapy may be needed.

After BH3 profiling both healthy and AML cells, the authors wrote,"We found that mitochondrial priming measured by BH3 profiling was a determinant of initial response to induction [initial] chemotherapy, relapse following remission, and requirement for allogeneic bone marrow transplantation."

In addition to the new test method, the team also found AML cells rely on a signal from the BCL-2 protein for survival. Drugs that block the BCL-2 protein are being tested in humans.

Dr. Letai says these drugs might be useful in nudging cancer cells to self-destruct, and then “you could come in and finish the cancer cells off with chemotherapy.”

As far as the status of this procedure, Dr. Letai said in a news release, “We plan to confirm this in independent experiments, and then test its performance prospectively in clinical trials to see if we can use it to do a better job of assigning individualized therapy in AML."

This study was published in the Oct. 12 issue of the journal Cell. Funding for the research came from the National Institutes of Health.

 Dr. Letai  was a cofounder and formerly served on the scientific advisory board of Eutropics Pharmaceuticals, which has a license for BH3 profiling.

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Review Date: 
October 23, 2012