Acute myeloid leukemia (AML) is a hematopoietic neoplasia characterized by the rapid, clonal growth of the myeloid lineage of blood cells. Approximately 15,000 adults in the United States will be diagnosed with AML and 10,500 will succumb to their disease this year. Despite advances in understanding the etiology and biology of the disease, the treatment of AML has not changed drastically over the past 40 years. Even though 70% of patients achieve a complete remission following initial induction chemotherapy, the majority of these patients eventually relapse. The relapsed AML is often more aggressive and refractory to standard chemotherapy. A major problem with the current treatment of relapsed/refractory AML is that besides cytogenetics and genetic mutations, there is a lack of predictive biomarkers to guide treatment. The Letai laboratory developed a tool called BH3 profiling which measures the pro-apoptotic and anti- apoptotic proteins which control mitochondrial apoptosis to determine the relative """"""""priming"""""""" level of many cancer cells including AML. We have shown that AML cells that are primed are closer to the death threshold and are more chemosensitive compared to unprimed cells which are more chemoresistant. Currently, we lack a complete understanding of the pathways that control the relative priming of AML cells. If we can identify the pathways that regulate mitochondrial priming in AML, then we can manipulate these pathways to increase priming in otherwise low primed cells, enhancing our ability to kill them. Therefore, the overall goal of this project is to determine the pathways upstream of the mitochondria that regulate priming. Specifically, we propose to validate the use of a novel tool, dynamic BH3 profiling, to identify pathways whose inhibition increases AML apoptotic priming, (Aim 1) as well as to compare pathway dependencies upstream of the mitochondria in pre-treatment and relapsed AML (Aim 2). We also will use BH3 profiling to measure anti- apoptotic dependencies in order to direct treatment of AML via selective Bcl-2 inhibition (Aim 3). The completion of these studies will identify novel therapeutic strategies for the treatment of AML as well as provide a better understanding of the molecular biology that drives relapsed AML. To achieve these goals, the environment of Harvard Medical School/Dana Farber Cancer Institute and the expertise of Dr. Letai and fellow lab members have provided me with extensive training in both the techniques used and the study of mitochondrial apoptosis to understand the upstream regulators that control mitochondrial priming in AML.
This proposal will provide insights into the upstream signaling pathways as well as the anti-apoptotic dependencies that control mitochondrial apoptosis in AML cell lines and primary samples. Elucidating the mechanisms which control apoptosis in AML may ultimately identify novel therapeutic strategies for the treatment of AML, as well as provide a better understanding of the molecular biology that drives relapsed AML.
|Gutierrez-Martinez, Paula; Hogdal, Leah; Nagai, Manavi et al. (2018) Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nat Cell Biol 20:413-421|