Mitochondrial Apoptotic Sensitivity in Predicting Acute Myeloid Leukemia Response

Harvard Medical School, Boston MA

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Abstract

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Current research suggests that cancer consists of a mixture of malignant cells with potentially different drug sensitivity. Most significantly, the CD34? subset of progenitor acute myeloid leukemia (AML) cells are purported to survive drug treatment and contribute to cancer relapse. This project assesses how each AML cell survives death cues triggered by the presence of chemotherapeutic drugs and may open avenues for killing the resistant population.