Mitochondrial Apoptotic Sensitivity in Predicting Acute Myeloid Leukemia Response

Harvard Medical School, Boston MA

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Abstract

Adult acute myeloid leukemia is a type of cancer that exhibits a remarkably high initial treatment success rate yet many patients fail long-term due to relapse. One explanation is that a drug resistant subset may survive initial treatment to re-establish the cancer. It has been observed that resistance to chemotherapy correlates with apoptotic sensitivity determined by the interactions among the BCL-2 family members at the mitochondrion. Particularly, we have found in cell lines that diminished mitochondrial sensitivity to apoptotic signals in the form of peptides mimicking the Bcl-2 homology 3 (BH3) domains correlates with decreased cellular sensitivity to chemotherapy. To measure the mitochondrial sensitivity of individual cells in complex, heterogeneous primary AML samples, we have developed a FACS-based BH3 profiling technique based on these peptide responses. This proposal aims to test if BH3 profiling can serve as a prognostic predictor of patient outcome, detect resistant subsets and identify possible BCL-2 family anti-apoptotic members that can be targeted to selectively kill AML cells but not important normal hematopoietic progenitors. Furthermore, since the BH3 peptides specifically kill by inhibiting certain anti-apoptotic BCL-2 family members, the effectiveness of killing by certain peptides can show which BCL-2 members would be good candidates for future drug targeting.