Abstract
BackgroundEffectiveness of L-asparaginase administration in acute lymphoblastic leukemia treatment is mirrored in the overall outcome of patients. Generally, leukemia patients differ in their sensitivity to L-asparaginase; however, the mechanism underlying their inter-individual differences is still not fully understood. We have previously shown that L-asparaginase rewires the biosynthetic and bioenergetic pathways of leukemia cells to activate both anti-leukemic and pro-survival processes. Herein, we investigated the relationship between the metabolic profile of leukemia cells and their sensitivity to currently used cytostatic drugs.MethodsAltogether, 19 leukemia cell lines, primary leukemia cells from 26 patients and 2 healthy controls were used. Glycolytic function and mitochondrial respiration were measured using Seahorse Bioanalyzer. Sensitivity to cytostatics was measured using MTS assay and/or absolute count and flow cytometry. Mitochondrial membrane potential was determined as TMRE fluorescence.ResultsUsing cell lines and primary patient samples we characterized the basal metabolic state of cells derived from different leukemia subtypes and assessed their sensitivity to cytostatic drugs. We found that leukemia cells cluster into distinct groups according to their metabolic profile. Lymphoid leukemia cell lines and patients sensitive to L-asparaginase clustered into the low glycolytic cluster. While lymphoid leukemia cells with lower sensitivity to L-asparaginase together with resistant normal mononuclear blood cells gathered into the high glycolytic cluster. Furthermore, we observed a correlation of specific metabolic parameters with the sensitivity to L-asparaginase. Greater ATP-linked respiration and lower basal mitochondrial membrane potential in cells significantly correlated with higher sensitivity to L-asparaginase. No such correlation was found in the other cytostatic drugs tested by us.ConclusionsThese data support that cell metabolism plays a prominent role in the treatment effect of L-asparaginase. Based on these findings, leukemia patients with lower sensitivity to L-asparaginase with no specific genetic characterization could be identified by their metabolic profile.
Highlights
Effectiveness of L-asparaginase administration in acute lymphoblastic leukemia treatment is mirrored in the overall outcome of patients
Cell culture Human B-cell precursor leukemia cell lines (BCP-acute lymhoblastic leukemia (ALL); TOM-1, HB11;19, RS4;11, UOC-B6, REH, SUP-B15, NALM6), T-cell leukemia cell lines (HPB-ALL, CCRFCEM, JURKAT, MOLT-4), acute myeloid leukemia (AML) cell lines (MV4;11, KASUMI-1, NB-4, THP-1, MOLM-13) and cell lines derived from the blast crisis of chronic myeloid leukemia (CML), which manifest as AML (K-562, LAMA-84) and as ALL (BV-173), were used (Table S1)
Characterization of the basal metabolic state of leukemia cell lines We used 19 human leukemia cell lines of different origin (8 BCP-ALL (ALL derived from B-lymphocytes; 1 BCPALL originated from a CML blast crisis), 4 T-ALL and 7 of myeloid origin (5 AML; 2 CML blast crisis manifesting as AML)); in all of them, we determined glycolytic function, mitochondrial respiration and fatty acid oxidation (FAO) (Figure S1)
Summary
Effectiveness of L-asparaginase administration in acute lymphoblastic leukemia treatment is mirrored in the overall outcome of patients. Leukemia patients differ in their sensitivity to L-asparaginase; the mechanism underlying their inter-individual differences is still not fully understood. Leukemia is the most common malignancy and the second most frequent general cause of childhood death. It is classified as acute lymphoid of the B- or T-lineage being the most prevalent type in children, and as acute myeloid. The standardized treatment protocols consist of the same repertoire of cytostatic drugs which have been used for the past decades. They differ in the drug dosage, the time of administration and in the drug combinations. Understanding the mechanism of action and being able to predict the impaired effect of commonly administered drugs is crucial for improving patient outcomes
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