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Glutathione in childhood acute leukaemias
P Kearns1, R Pieters, M M Rottier
1Department of Paediatric Haematology and Oncology, Free University Hospital, Amsterdam, The Netherlands.
Insights
High glutathione (GSH) levels in childhood acute leukaemia blasts correlate with poor prognosis and treatment resistance. Modulating GSH synthesis may improve chemotherapy effectiveness in acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML).
Area of Science:
- Pediatric Oncology
- Molecular Biology
- Cancer Research
Background:
- Mechanisms of treatment resistance in childhood acute leukaemias (ALL and AML) remain poorly understood.
- Glutathione (GSH), an intracellular thiol, is implicated in cytotoxic drug resistance, cell proliferation, and apoptosis.
Purpose of the Study:
- To investigate the hypothesis that glutathione (GSH) levels in blast cells are a key determinant of treatment response in childhood acute leukaemia.
- To assess the prognostic value of GSH in acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML).
Main Methods:
- Quantification of total glutathione (GSH) levels in cryopreserved blast cells from 62 children with ALL and 13 with AML.
- Correlation analysis between GSH levels and clinical parameters such as presenting white cell count (WCC).
Main Results:
- In ALL, elevated GSH levels were associated with a poorer prognosis.
- A positive correlation was observed between GSH levels and presenting white cell count (WCC) in ALL.
- GSH levels were significantly higher in T-lineage ALL compared to B-lineage ALL, and higher in AML blasts compared to ALL blasts.
Conclusions:
- Glutathione (GSH) levels serve as a potential prognostic indicator in childhood leukaemia.
- Elevated GSH may represent a mechanism contributing to treatment failure in childhood acute leukaemias.
- Targeting GSH synthesis could potentially enhance chemosensitivity and improve treatment outcomes.
Abstract:
In order to test the hypothesis that glutathione (GSH) is an important determinant of treatment response in childhood acute leukaemia, blast cell GSH levels were studied in a cohort of children with acute lymphoblastic (ALL) and acute myeloid (AML) leukaemia. In both ALL and AML, several indicators of poor prognosis are well established but the underlying molecular mechanisms leading to resistant disease are still poorly understood. GSH is an intracellular thiol implicated in the development of cytotoxic drug resistance and appears to be involved in the control of cell proliferation and apoptosis. In this study, total GSH was measured in cryopreserved blasts from 62 childhood ALL and 13 AML patients. In ALL, high GSH levels were associated with a relatively poor prognosis. A positive correlation was demonstrated between the GSH level and presenting white cell count (WCC). GSH levels were significantly higher in T lineage ALL compared with B lineage and in AML blasts compared with ALL. These results are supportive of GSH as prognostic indicator in childhood leukaemia and may suggest one mechanism of treatment failure. They imply that it may be possible to improve chemosensitivity by the use of known modulators of GSH synthesis.