New tool determines "readiness to die" of leukemia cells

A novel method has been developed to determine how ready acute myeloid leukemia (AML) cells are to die. This discovery may help to more effectively choose treatment options for patient with AML, and may lead to improved tests that will 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, yet may benefit from a bone marrow transplant.

Clinicians currently try to predict the outcome for an AML patient by assessing the pathological features of the cancer cells and if the cells have certain mutations that suggest a poorer response. These indicators do not provide a biological explanation for the different responses of patients to treatment.

The new method determines the degree to which an individual patient's AML cells are “primed to die” by apoptosis, which is programmed cell death. When cancer cells are well along the path to self-destruction, chemotherapy is more effective. Those patients whose leukemia cells are less primed are more likely to suffer fatal relapse without a bone marrow transplant.

The new approach uses BH3 profiling to measure how ready the mitochondria are to unleash chemical compounds that cause the cell to destroy itself, which is apoptosis. “Death molecules” trigger apoptosis, which eliminates unneeded or dangerously damaged cells from the body. This readiness for apoptotic self-destruction is mitochondrial priming.

BH3 profiling involves exposing cancer cells to BH3 molecules, which mimic protein death signals in the body. Those cancer cells whose mitochondrial membrane is rapidly and easily disrupted are considered highly primed for death. When mitochondria strongly resist the disruption, the leukemia cells are further from self-destruction and less likely to respond to chemotherapy.

The study, published in Cell (2012;151[2]:344-355), described 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.” 

Anthony Letai, MD, PhD, of Dana-Farber Cancer Institute and senior author, explained how it is useful to know if a patient is likely to have a complete response to chemotherapy so decisions about chemotherapy can be personalized, 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.”

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