Targeting the Metabolic Drivers of Chemo Resistance in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is one of the most challenging childhood cancers to treat. Induction chemotherapy remains the standard of care, but the incidence of refractory and relapsed AML is high. It remains unclear how certain AML cells manage to survive the extreme stress of chemotherapy. The search for specific genetic mutations that lead to therapy resistance has thus far not been successful. While mutations may certainly play a role, cells have other systems to protect them from stress, such as shifting metabolic programs.
I hypothesize that chemo resistance in AML arises at the time of maximal selection pressure, with the residual cells manifesting distinctive metabolic features that enable their survival under the extreme stress of chemotherapy. By defining the metabolism of the residual, resistant cells in vivo using a new methodology, I have identified glutamine metabolism as a candidate pathway supporting chemo resistance in AML cells. In the current project, I aim to (i) dissect the mechanism by which activation of glutamine metabolism confers chemo resistance, (ii) develop a therapeutic strategy to eradicate chemo resistant AML cells by targeting glutamine metabolism, and (iii) explore the dynamics of glutamine metabolism during chemotherapy treatment in vivo using intravital microscopy. These studies will offer a new paradigm for how chemo resistance arises and will further deepen our understanding of the link between metabolism and cellular stress. The developed toolset will furthermore be of great value for future studies into cell metabolism in vivo.