Targeting amino acid metabolism and pyrimidine synthesis to overcome acute myeloid leukemia chemoresistance
Final Report Abstract
Acute myeloid leukemia (AML) is a complex and difficult-to-treat cancer. While high-dose chemotherapy is a standard approach, many patients relapse after an initial response with devastating consequences. In our research, we studied the strategies employed by AML cells to rewire their metabolism to survive the harsh conditions created by chemotherapy. Abundance of metabolites can change the activity of enzymes without being reflected on a genetic, transcriptome or protein level. To understand the adaptations driving leukemia cell survival in chemotherapy, it is critical to investigate dynamic alterations on the metabolite level. Our investigations revealed that AML cells undergo a metabolic shift, notably in their handling of aminoacids. These amino acids play a pivotal role in the adaptive responses of AML cells to chemotherapy-induced stress. To gain a deeper understanding, we are conducting in vivo stable isotope tracing studies in mice harboring AML and subjected to chemotherapy. Our aim is to pinpoint the specific steps in BCAA metabolism where AML cells exhibit the highest degree of dependency. Importantly, our research spans mouse and human AML (patient-derived xenografts) characterized by different driver mutations. Ultimately, we intend to translate our findings into clinical applications by analyzing bone marrow samples obtained from patients at the time of diagnosis and after undergoing initial chemotherapy. If our validation studies prove successful, they will provide a strong scientific basis for developing targeted therapies that focus on amino acid metabolism. This promising avenue holds the potential to enhance treatment outcomes and improve survival rates for AML patients in the future.
Publications
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Cell of origin epigenetic priming determines susceptibility toTet2mutation. Cold Spring Harbor Laboratory.
Schiroli, Giulia; Kartha, Vinay; Duarte, Fabiana M.; Kristiansen, Trine A.; Mayerhofer, Christina; Shrestha, Rojesh; Earl, Andrew; Hu, Yan; Tay, Tristan; Rhee, Catherine; Buenrostro, Jason D. & Scadden, David T.
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Clonal hematopoiesis in older patients with breast cancer receiving chemotherapy. JNCI: Journal of the National Cancer Institute, 115(8), 981-988.
Mayerhofer, Christina; Sedrak, Mina S.; Hopkins, Judith O.; Li, Tianyu; Tayob, Nabihah; Faggen, Meredith G.; Sinclair, Natalie F.; Chen, Wendy Y.; Parsons, Heather A.; Mayer, Erica L.; Lange, Paulina B.; Basta, Ameer S.; Perilla-Glen, Adriana; Lederman, Ruth I.; Wong, Andrew R.; Tiwari, Abhay; McAllister, Sandra S.; Mittendorf, Elizabeth A.; Gibson, Christopher J. ... & Miller, Peter G.
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PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy. Blood, 142(24), 2079-2091.
Miller, Peter G.; Sperling, Adam S.; Mayerhofer, Christina; McConkey, Marie E.; Ellegast, Jana M.; Da, Silva Carmen; Cohen, Drew N.; Wang, Chuqi; Sharda, Azeem; Yan, Ni; Saha, Subha; Schluter, Cameron; Schechter, Ilexa; Słabicki, Mikołaj; Sandoval, Brittany; Kahn, Josephine; Boettcher, Steffen; Gibson, Christopher J.; Scadden, David T. ... & Ebert, Benjamin L.
