Abstract
Abstract Hematopoietic stem cells (HSCs) undergo self-renewal or differentiation to generate the many myeloid and lymphoid cells. When dysregulated, cancers such as Acute myeloid leukemia (AML) may develop. AML is characterized by expansion and proliferation of undifferentiated myeloid cells that derive from a Leukemic Stem Cell (LSC) population. AML is the most common form of leukemia with 19,520 new cases in 2018, with an adult five-year survival rate of 24%. Here, we examine a newfound relationship between glutamine metabolism, epigenetics, and targeted differentiation of LSCs in AML to promote disease clearance. Glutamine is catalyzed by glutaminase (GLS) to supply α-ketoglutarate (αKG) to the tricarboxylic acid (TCA) cycle and as substrate to demethylase enzymes. We hypothesize that glutamine metabolism plays an integral role in balancing the fate decision of LSCs and that targeting GLS will impact epigenetic modifications and gene expression to affect cell fate. Glutaminase knockout may also be exploited to promote differentiation of AML LSCs. Preliminary data demonstrates the link between epigenetics and metabolism in AML. We profiled three different AML cell lines’ metabolic responses to INCB54329, an inhibitor of bromodomain proteins. We present a heterogeneous response to INCB54329 in oxygen consumption rate, extracellular acidification rate, reactive oxygen species generation, and mitochondrial mass and membrane potential. The precise function of glutaminolysis in hematopoiesis remains unclear. Unraveling the link between glutamine metabolism, epigenetic modifications, and stem cell function presents a novel therapeutic opportunity for various hematologic malignancies, chief among them acute myeloid leukemia.
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