New tool determines leukemia cells' 'readiness to die,' may guide clinical care
Researchers at Dana-Farber Cancer Institute have developed a novel method for determining how ready acute myeloid leukemia (AML) cells are to die, a discovery that may help cancer specialists to choose treatments option more effectively for their patients who have AML. In a study published in the Oct. 12 issue of the journal Cell, the researchers report that their findings may lead to improved tests to predict which patients successfully treated for AML can continue in remission with standard chemotherapy alone, and which patients are likely to relapse despite additional treatment, but might benefit from a bone marrow transplant.
Anthony Letai, MD, PhD, senior author of the paper, said the study's results also help to explain the "therapeutic index" of AML chemo drugs: That is, how a patient's normal blood-forming stem cells can survive chemotherapy doses that kill the leukemia cells.
Unlike current predictive tools, the new method determines the degree to which an individual patient's AML cells are "primed to die" by apoptosis, or programmed cell death. Chemotherapy is more effective when the cancer cells are well along the path to self-destruction, while patients with less-primed leukemia cells are more likely to suffer fatal relapse without a bone marrow transplant, said the researchers.
"Our data suggest that applying our assay in addition to conventional indicators yields a much better predictive tool," said Letai. "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."
According to the American Cancer Society, an estimated 13,780 cases of AML will be diagnosed in the United States this year, and more than 10,000 people are expected to die from AML, making it the most lethal form of leukemia in the U.S.
Currently, clinicians try to predict an AML patient's outcome by assessing the cancer cells' pathological features and whether the cells contain certain mutations that suggest a poorer response. But these indicators do not provide a biological explanation for patients' differing responses to treatment, noted Letai.
The method described in the new study takes a different approach, first described by Letai in 2011 paper. It employs a technique called "BH3 profiling" to measure the readiness of mitochondria – tiny organelles within the cell – to unleash chemical compounds that cause the cell to destroy itself. The self-destruction process, called apoptosis, is triggered by "death molecules," whose mission is to eliminate unneeded or dangerously damaged cells from the body. The study's authors called this readiness for apoptotic self-destruction "mitochondrial priming."
BH3 profiling involves exposing cancer cells to BH3 molecules, which mimic the protein death signals in the body. If the cancer cells' mitochondria membrane is rapidly and easily disrupted, then the cells are considered to be highly primed for death. If the mitochondria strongly resist the disruption, the leukemia cells are further from self-destruction and less likely to respond to chemotherapy.
Applying the method to stored AML patient samples, "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," the authors wrote.
Moreover, knowing whether a patient is likely to have a complete response to chemotherapy would be also very useful in personalizing chemotherapy decisions even when bone marrow transplant is not a consideration. "In elderly patients with AML, chemotherapy can be very toxic with an increased risk of fatal complications," said Letai. "You don't want to give chemotherapy unless you know whether it will benefit. Now we can predict who will benefit from it and who won't—and should receive an alternative treatment."
The scientists measured mitochondrial priming in normal hematopoietic stem cells that generate all the cells of a healthy person. These stem cells were found to be less-primed for self-destruction than the leukemia cells that were readily killed by chemotherapy. Patients with AML who had responded poorly to chemotherapy had cancer cells that were even less-primed than normal hematopoietic stem cells. Thus it was not surprising that doses of chemo that spared their blood stem cells were not effective against their leukemia.
However, the researchers found that AML cells – even the treatment-resistant ones – had a potential weakness that might be exploited. Compared with normal blood stem cells, the AML cells were more dependent for survival on molecular signals generated by the BCL-2 protein. Experimental drugs that can block BCL-2 signals are being tested in humans. This suggests, said Letai, that such drugs given to AML patients could move the cancer cells closer to the point of self-destruction.
"And then you could come in and finish the cancer cells off with chemotherapy," Letai said. First author of the report is Thanh-Trang Vo, PhD, formerly at Dana-Farber. Co-authors are from Dana-Farber, Harvard Medical School, and Memorial Sloan Kettering Cancer Center.
Journal reference: Cell
Provided by Dana-Farber Cancer Institute
- Research predicts how cancers will respond to chemo, rewrites old theory of why chemo works Oct 27, 2011 | not rated yet | 0
- Study identifies drug resistance of CLL in bone marrow and lymph nodes Dec 06, 2010 | not rated yet | 0
- Two-faced leukemia? Dec 12, 2011 | not rated yet | 0
- Cell death researchers identify new Achilles heel in acute myeloid leukemia Jan 17, 2012 | not rated yet | 0
- Drug makes leukemia more vulnerable to chemo Mar 20, 2012 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
In recent years, microRNAs (miRNAs) and other non-coding RNAs are small molecules that help control the expression of specific proteins. In recent years they have emerged as disease biomarkers. miRNA profiles have been used ...
Cancer 9 hours ago | not rated yet | 0
Cancer cells spread and grow by avoiding detection and destruction by the immune system. Stimulation of the immune system can help to eliminate cancer cells; however, there are many factors that cause the immune system to ...
Cancer 9 hours ago | not rated yet | 0
Researchers from London's Kingston University have begun a two-year study which could help prolong the lives of people with colorectal tumours.
Cancer 13 hours ago | 5 / 5 (1) | 0
Transformative research from Western University has identified new hormones in the body which may suppress breast cancer and stimulate the regression of breast tumors.
Cancer 13 hours ago | 5 / 5 (1) | 0
(Medical Xpress)—Curtin University researchers have found evidence that targeting specific cells in the body can reverse the effects of cancer on the immune system.
Cancer 14 hours ago | 5 / 5 (3) | 0
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
13 hours ago | 5 / 5 (3) | 0 |
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
7 hours ago | 3 / 5 (2) | 0 |
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
10 hours ago | 5 / 5 (2) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
10 hours ago | 5 / 5 (3) | 0 |
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
7 hours ago | not rated yet | 0
(Medical Xpress)—Patients with diabetes who are depressed are much more likely to develop episodes of dangerously low blood sugars, or hypoglycemia, than are those who are not depressed, a new study has ...
14 hours ago | not rated yet | 0 |