Gene expression ratio as a predictive determinant of nelarabine chemosensitivity in T-lymphoblastic leukemia/lymphoma

Abstract

Background: Nelarabine has been used for the treatment of T-cell malignancies including T-acute lymphoblastic leukemia (T-ALL)/T-lymphoblastic lymphoma. However, the mechanisms that underlie the susceptibility or resistance to nelarabine have not been fully elucidated. The aim of this study was to determine the significance of nelarabine transport and metabolism in the context of nelarabine cytotoxicity.

Procedure: The expression profiles of six genes in the nelarabine pathway were analyzed in blast cells from six patients with T-ALL as well as in three T-ALL cell lines. In vitro cytotoxicity (LC₅₀ of 9-β-d-arabinofuranosylguanine [ara-G]) was evaluated.

Results: The mRNA expression of ENT1, DCK, CDA, NT5C2, RRM1, and RRM2 in patients showed inter-individual variability and was not correlated with the LC₅₀ of ara-G. However, the ratio of (ENT1 × DCK)/(CDA × RRM1) expression was significantly correlated with LC₅₀ (r = -0.831, P = 0.0405).

Conclusions: Chemosensitivity to nelarabine is influenced by the balance of the expression of these four genes, and the ratio of their expression predicts the response of T-cell malignancies to nelarabine.

Keywords: Chemosensitivity; T-acute lymphoblastic leukemia; gene expression; gene expression ratio; nelarabine.