Project Term
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Project Summary
Acute myeloid leukemia (AML) is a heterogeneous group of diseases that require complex therapy and are difficult to cure. AML is caused by the accumulation of DNA mutations in blood stem cells that alter their normal blood production. However, our groups have demonstrated that these genetic changes are not sufficient to cause leukemia. Rather, the cells must acquire additional, adaptive changes in cellular metabolism which includes the biochemical reactions that regulate cell growth. Many of these biochemical reactions are regulated by mitochondria, which are referred to as the powerhouse of the cell. We have demonstrated that these metabolic adaptations make AML cells resistant to chemotherapy. In particular, AML cells adaptively increase their mitochondrial mass and energy production after chemotherapy. The biochemical reactions involved are complex and appear to vary between AML cells and normal blood stem cells. This suggests that if we fully understand the exact metabolic changes that regulate chemotherapy resistance, we can improve the efficacy of such therapy by inhibiting those metabolic responses. To address this complex problems we have assembled a team of four investigators and three Core leaders with complementary skills in understanding AML metabolism, biology and chemotherapy resistance. This group is uniquely capable due to their complementary skills in bringing metabolic targeting to the treatment of AML.
Lay Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by different genetic mutations. Several of these mutations can be “targeted” with current therapies but most patients receive cytotoxic chemotherapy which is toxic and typically not curative. Thus, new ways of thinking about chemotherapy resistance are necessary. Our group of investigators has pioneered the concept that altered cellular metabolism is essential to AML biology and chemotherapy resistance. This work has focused on the cellular component, mitochondria, and its major biochemical process, oxidative phosphorylation (OxPhos). However, trying to inhibit OxPhos directly in humans has proven toxic. Thus, we have undertaken to understand AML metabolism in primary human cells in greater detail that will allow us to develop and test non-toxic therapies. Projects 1 and 2 have dissected other biochemical processes that are regulated by mitochondria. These studies have lead to a focus on an essential molecule, glutathione or GSH. Project 1 is studying how GSH is added to other proteins to regulate their activity and how these regulatory steps alter chemoresistance. Project 2 is focused on the most fatal of AML’s, the sub-type with mutations in the TP53 gene. They describe here that TP53 mutant AML is dependent on GSH for regulation of a mitochondrial byproduct known as reactive oxygen species. Both of these projects will work together to define the exact metabolic functions in AML cells that are necessary for chemoresistance. Projects 3 and 4 broaden the scope of thinking about AML and its metabolic regulation. Project 3 has asked the question, how AML cells remain healthy mitochondria that have the adaptive capabilities described by Projects 1 and 2. Strikingly, Project 3 has found that AML cells receive healthy mitochondria from bone marrow cells called stromal cells. These stromal cells also take back unhealthy mitochondria from AML cells. Project 3 will test the hypothesis that this process can be inhibited to improve AML therapy. Finally, it has become clear from work by us and others, that AML metabolism, as well as its genetics, is heterogeneous. Project 4 has begun to work on a sub-type of AML, patients with a mutation in a gene called NRAS. Project 4 has also recently developed a mouse model of AML with NRAS mutations and shown that NRAS mutant AML mice produce unique metabolites. Project 4 will continue to study the metabolomics of NRAS mutant AML by comparing it to other sub-types of AML (in mice and in human cells) and by seeing how the metabolism changes during therapy. Thus, together, this group will provide a robust understanding of leukemic cell metabolism in diverse sub-types, how that metabaolism changes during therapy and whether it is consistently dependent on mitochondrial transfer from stromal cells. As we develop this understanding, we will test drugs that inhibit these steps in our xenotransplant system that should lead to novel human trials.
Program
