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Open Access 01-12-2020 | Acute Myeloid Leukemia | Research article

Metabolic profile of leukemia cells influences treatment efficacy of L-asparaginase

Authors: Katerina Hlozkova, Alena Pecinova, Natividad Alquezar-Artieda, David Pajuelo-Reguera, Marketa Simcikova, Lenka Hovorkova, Katerina Rejlova, Marketa Zaliova, Tomas Mracek, Alexandra Kolenova, Jan Stary, Jan Trka, Julia Starkova

Published in: BMC Cancer | Issue 1/2020

Abstract

Background

Effectiveness 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.

Methods

Altogether, 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.

Results

Using 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.

Conclusions

These 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.

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Title: Metabolic profile of leukemia cells influences treatment efficacy of L-asparaginase
Authors: Katerina Hlozkova
Alena Pecinova
Natividad Alquezar-Artieda
David Pajuelo-Reguera
Marketa Simcikova
Lenka Hovorkova
Katerina Rejlova
Marketa Zaliova
Tomas Mracek
Alexandra Kolenova
Jan Stary
Jan Trka
Julia Starkova
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Leukemia
Published in: BMC Cancer / Issue 1/2020
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-020-07020-y

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