Impact of acute lymphoblastic leukemia induction therapy: findings from metabolomics on non-fasted plasma samples from a biorepository

Saito, Toshie; Wei, Yue; Wen, Li; Srinivasan, Chaitanya; Wolthers, Benjamin Ole; Tsai, Cheng‐Yu; Harris, Marian H.; Stevenson, Kristen E.; Byersdorfer, Craig A.; Oparaji, Judy-April; Fernandez, Christian A.; Mukherjee, Amitava; Abu‐El‐Haija, Maisam; Agnihotri, Sameer; Schmiegelow, Kjeld; Showalter, Megan R.; Fogle, Paul; McCulloch, Scott; Contrepois, Kévin; Silverman, Lewis B.; Ding, Ying; Husain, Sohail Z.

doi:10.1007/s11306-021-01814-2

Cited by 8 publications

(8 citation statements)

References 48 publications

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“…Our results are consistent with previous studies investigating the effect of leucine, isoleucine, or valine deprivation on fat mass and lipid metabolism 47 , 48 . Our results are also consistent with a recent metabolomics study of pediatric plasma samples collected after the completion of the induction phase of leukemia therapy, which found that fatty acid concentrations were increased after induction and that lipid metabolism was the most significantly altered pathway in a pathway enrichment analysis 49 . Interestingly, we see a decrease in hepatic triglyceride levels and ORO staining ( Fig.…”

Section: Discussionsupporting

confidence: 92%

“…1 A, Day 7). While our clinical research supports mobilization of lipid-based moieties, particularly the membrane lipid phosphatidylethanolamine (PE) plasmalogen 49 , additional studies are required to elucidate the hepatic lipids accumulating after PEG-ASNase treatment. Altogether, our results, and that of others, support that the fatty liver induced by PEG-ASNase is most likely due to hepatic fatty acid accumulation following drug-induced adipose tissue lipolysis.…”

Section: Discussionmentioning

confidence: 94%

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Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

Kumar

Hoshitsuki

Rathod

et al. 2021

Acta Pharmaceutica Sinica B

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PEGylated- l -asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β -oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara , Lcad/Mcad , Hadhb , Apob100 , and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 94%

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

Kumar

Hoshitsuki

Rathod

et al. 2021

Acta Pharmaceutica Sinica B

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“…Glucocorticoids have been used for more than 50 years as a central component of therapy. Glucocorticoid-mediated reduction of de novo nucleotide synthesis and abnormal lipid metabolism are prevalent in B-ALL chemotherapy [ 23 , 24 ]. Therefore, it is crucial to find therapeutic targets that act on metabolic processes.…”

Section: Discussionmentioning

confidence: 99%

1,5-Anhydroglucitol promotes pre-B acute lymphocytic leukemia progression by driving glycolysis and reactive oxygen species formation

Zhu

Dong

et al. 2023

BMC Cancer

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Background Precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the most common hematological malignancy in children. Cellular metabolic reorganization is closely related to the progression and treatment of leukemia. We found that the level of 1,5-anhydroglucitol (1,5-AG), which is structurally similar to glucose, was elevated in children with pre-B ALL. However, the effect of 1,5-AG on pre-B ALL was unclear. Here, we aimed to reveal the roles and mechanisms of 1,5-AG in pre-B ALL progression. Methods The peripheral blood plasma level of children with initial diagnosis of pre-B ALL and that of healthy children was measured using untargeted metabolomic analysis. Cell Counting Kit-8 assay, RNA sequencing, siRNA transfection, real-time quantitative PCR, and western blot were performed using pre-B ALL cell lines Reh and HAL-01. Cell cycle, cell apoptosis, ROS levels, and the positivity rate of CD19 were assessed using flow cytometry. Oxygen consumption rates and extracellular acidification rate were measured using XFe24 Extracellular Flux Analyzer. The lactate and nicotinamide adenine dinucleotide phosphate levels were measured using kits. The effect of 1,5-AG on pre-B ALL progression was verified using the In Vivo Imaging System in a xenotransplantation leukemia model. Results We confirmed that 1,5-AG promoted the proliferation, viability, and intracellular glycolysis of pre-B ALL cells. Mechanistically, 1,5-AG promotes glycolysis while inhibiting mitochondrial respiration by upregulating pyruvate dehydrogenase kinase 4 (PDK4). Furthermore, high levels of intracellular glycolysis promote pre-B ALL progression by activating the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Conversely, N-acetylcysteine or vitamin C, an antioxidant, effectively inhibited 1,5-AG-mediated progression of leukemia cells. Conclusions Our study reveals a previously undiscovered role of 1,5-AG in pre-B ALL, which contributes to an in-depth understanding of anaerobic glycolysis in the progression of pre-B ALL and provides new targets for the clinical treatment of pre-B ALL.

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“…The plasma samples needed to be frozen within 24 hours, and only the DFCI parent site at the time could assure this sample processing requirement. Blood collection, sample preparation for metabolomic profiling, metabolite detection, and data processing were described in our previous study ( 55 ). Briefly, deidentified plasma samples were obtained from individuals enrolled in one of two consecutive clinical trials conducted by the DFCI ALL Consortium: DFCI 05-001 ( 19 ) and DFCI 11-001 ( 20 ).…”

Section: Methodsmentioning

confidence: 99%

A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis

et al. 2023

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Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.

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Impact of acute lymphoblastic leukemia induction therapy: findings from metabolomics on non-fasted plasma samples from a biorepository

Cited by 8 publications

References 48 publications

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

1,5-Anhydroglucitol promotes pre-B acute lymphocytic leukemia progression by driving glycolysis and reactive oxygen species formation

A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis

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