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Potential mechanisms of resistance to cytarabine in AML patients
Carlos M Galmarini1, Xavier Thomas, Fabien Calvo
1Unité INSERM 453, Laboratoire de Cytologie Analytique, Faculté de Médecine Rockefeller, 8, avenue Rockefeller, 69373 Lyon Cedex 08, France. fgalma@rockefeller.univ-lyon.fr
Abstract:
To determine whether the human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), cytoplasmic 5'-nucleotidase (5NT), cytidine deaminase (CDD), topoisomerase I (TOPO I) and topoisomerase II alpha (TOPO II) are involved in clinical resistance to cytarabine (ara-C), we analyzed the level of expression of these parameters by reverse transcriptase polymerase chain reaction (rt-PCR), at diagnosis in the blast cells of 77 acute myeloid leukemia (AML) patients treated with ara-C, including 31 for whom samples were collected at first relapse. By univariate and/or multivariate analyses, patients with expression of 5NT or hENT1 deficiency at diagnosis had significantly shorter disease-free survival (DFS) and overall survival (OS). These results suggest that expression of 5NT and reduced hENT1 in leukemic blasts at diagnosis are correlated with clinical outcome and may play a role in resistance mechanisms to ara-C in patients with AML.
Insights
Cytarabine (ara-C) resistance in acute myeloid leukemia (AML) may be linked to specific gene expressions. High cytoplasmic 5-nucleotidase (5NT) and low human equilibrative nucleoside transporter 1 (hENT1) expression in leukemia cells at diagnosis correlate with poorer patient survival.
Area of Science:
- Biochemistry
- Molecular Biology
- Hematology
Background:
- Cytarabine (ara-C) is a key chemotherapy agent for acute myeloid leukemia (AML).
- Mechanisms of ara-C resistance in AML are not fully understood.
- Several nucleoside transporters and metabolizing enzymes may influence ara-C efficacy.
Purpose of the Study:
- To investigate the role of human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), cytoplasmic 5'-nucleotidase (5NT), cytidine deaminase (CDD), topoisomerase I (TOPO I), and topoisomerase II alpha (TOPO II) in clinical ara-C resistance in AML.
- To correlate the expression levels of these molecules with patient outcomes.
Main Methods:
- Analysis of gene expression in blast cells from 77 AML patients using reverse transcriptase polymerase chain reaction (rt-PCR).
- Samples were collected at diagnosis and for 31 patients at first relapse.
- Univariate and multivariate analyses were performed to assess correlations with survival.
Main Results:
- Patients with high 5NT expression or deficient hENT1 expression at diagnosis showed significantly shorter disease-free survival (DFS).
- These patients also had significantly shorter overall survival (OS).
- Expression levels of dCK, CDD, TOPO I, and TOPO II were not significantly correlated with DFS or OS.
Conclusions:
- Expression of 5NT and reduced hENT1 in leukemic blasts at diagnosis are correlated with clinical outcomes in AML patients treated with ara-C.
- These factors may contribute to resistance mechanisms against ara-C in AML.
- Targeting or monitoring 5NT and hENT1 could potentially improve AML treatment strategies.