Role of gamma-glutamyl cysteine synthetase (gamma-GCS) gene expression as marker of drug sensitivity in acute myeloid leukemias.

Background: Elevated levels of glutathione (GSH) have been reported to play an important role in mediating chemoresistance in tumor cells. The regulation of gamma-glutamylcysteine synthetase (gamma-GCS) is one of the major determinants of GSH homeostasis. The aim of our study was to investigate gamma-GCS gene expression in patients affected by acute myeloid leukemia (AML).

Methods: A total of 64 AML samples, including 23 acute promyelocytic leukemia (APL or M3) cases, were included in the study. gamma-GCS mRNA levels were determined by real-time quantitative RT-PCR. All patients were evaluated at diagnosis, whereas post-treatment gamma-GCS mRNA levels were assessed at the end of the consolidation therapy in 16 cases.

Results: Our data showed that variable degrees of gamma-GCS expression were detectable in AML, likely reflecting disease heterogeneity; in particular, APL cases, compared to the other AML subsets, showed both significantly lower basal levels of gamma-GCS mRNA at presentation and significantly increased mRNA levels after treatment.

Conclusions: Decreased levels of gamma-GCS leading to reduced GSH may at least in part explain the higher sensitivity of APL to chemotherapy.