(ChemotherapyAdvisor) – A new profiling technique determines acute myeloid leukemia (AML) cells’ “readiness” for apoptotic cell death – and hence, their likely responses to chemotherapy, according to a preclinical study published in the journal Cell.
The technique measures cells’ mitochondrial priming by exposing them to BH3, an apoptotic signaling molecule from the BCL-2 protein family that targets the organelle membranes of mitochondria within cells.
“We found that mitochondrial priming measured by BH3 profiling was a determinant of initial response to induction chemotherapy, relapse following remission, and requirement for allogeneic bone marrow transplantation,” reported a research team led by senior author Anthony Letai, MD, PhD, of the Harvard Medical School and the Department of Medical Oncology at the Dana-Farber Cancer Institute in Boston.
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Healthy hematopoietic stem cells are less mitochondrially-primed for apoptosis than are leukemia cells that are vulnerable to chemotherapy-induced apoptosis, found the authors. But AML cells that did not respond well to chemotherapy were less mitochondrially primed than normal stem cells, they found.
BH3 molecules are part of the BCL-2 apoptosis pathway and trigger the release of pro-apoptosis signals in the mitochondrial cell membrane. The researchers found that all AML cells studied, regardless of their sensitivity to chemotherapy, are more dependent on BCL-2 proteins than are healthy hematopoietic stem cells — suggesting that BCL-2 antagonist therapies might prove useful in priming AML cells for better responses to chemotherapy, the authors noted.
“BH3 profiling identified BCL-2 inhibition as a targeted strategy likely to have a useful therapeutic index,” they wrote.
The findings could also prove to be a useful non-genetic biomarker for identifying which patients with AML are likely to benefit from chemotherapy, and which patients should be spared the toxicity of therapies unlikely to benefit them, the authors reported.
“BH3 profiling refines predictive information provided by conventional biomarkers currently in use and thus may itself have utility as a clinical predictive biomarker,” they reported. It “can provide information that can potentially be exploited for personalization of AML therapy in the application of BCL-2 antagonists, allogeneic bone marrow transplant, and conventional chemotherapy.”
