Elucidating metabolic vulnerabilities to improve outcomes in pediatric precursor B-cell acute lymphoblastic leukemia




Sweeney, Shannon Renee

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Cancer continues to be the leading cause of disease-related death in children. Improving treatment protocols and outcomes for pediatric leukemia patients is of critical importance as acute lymphoblastic leukemia (ALL) accounts for 25% of all childhood cancers. ALL five-year relative survival rates have improved significantly in recent decades. However, many survivors suffer severe chronic physiological and psychological health problems, as well as poor social and economic outcomes. These consequences exemplify the continuing need to develop targeted, less toxic alternative therapeutics. Metabolomics, an emerging tool for precision medicine, can be used to analyze intracellular and extracellular environments, metabolic response to treatment, and pathway regulation in order to expand our understanding of the molecular mechanisms that drive pediatric cancer biology and identify and evaluate novel therapeutics. This study applied metabolomics approaches to precursor B-cell ALL (BCP-ALL) which accounts for 80% of ALL cases in children and adolescents. First, high-throughput screening (HTS) was used to identify a synergistic combination of non-toxic therapeutic alternatives to chemotherapy. Metabolomics and metabolic flux analyses of dimethylaminoparthenolide (DMAPT) and shikonin (SHK) in BCP-ALL showed changes in amino acid, antioxidant, TCA cycle, and nucleotide metabolism. The shunting of glycolytic intermediates and glutaminolysis-related metabolites to support proliferation was inhibited by DMAPT and SHK leading to apoptosis in BCP-ALL cells. Second, bone marrow-derived leukemia cells were collected from pediatric BCP-ALL patients at diagnosis. Stratifying patients by cytogenetic anomalies yielded unique metabolic profiles. Aberrations at the IGH locus are associated with poor outcomes, but no clear therapeutic targets have been identified. Assessment of individual metabolites indicated that amino acids, amino acid-related compounds, and some sugars were more abundant in patients with IGH locus aberrations. Phosphatidylcholines, phosphatidylethanolamines, and polar compounds involved in lipid metabolism were also increased, while nucleotides, diglycerides, and triglycerides were decreased in the IGH group. Pathway interrogation confirmed metabolic dysregulation. HTS indicated IGH mutant sensitivity to HSP, proteasome, mTOR, and HDAC inhibitors. Together, these analyses indicate the flexibility and utility of metabolomics to elucidate the underlying biology of pediatric leukemia and evaluate novel therapeutics to improve quality of life and long-term outcomes for childhood leukemia patients and adult survivors.


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