NEW YORK (Reuters Health) - The high cure rate of acute megakaryocytic leukemia (AMkL) in Down syndrome children is attributable to the effects of GATA1 mutations on cytidine deaminase gene expression -- and therefore susceptibility to cytosine arabinoside -- according to a report in the February 2nd Journal of the National Cancer Institute.
“This is another example of how a genetic defect in a specific cancer, which is linked in some fashion to the development of the particular type of cancer, also makes them more responsive to specific treatments,” Dr. Jeffrey W. Taub from Children’s Hospital of Michigan, Detroit, Michigan told Reuters Health.
Blast cells from Down syndrome children are more sensitive to cytosine arabinoside (ara-C) than are blast cells from other children with AML, the authors explain, and mutations in GATA1, which regulates various target genes, have recently been reported in Down syndrome children with AMkL.
Dr. Taub and colleagues assessed the relationship between ara-C and GATA1 using the clinically relevant Down syndrome AMkL cell line CMK transfected with GATA1 cDNA.
CMK transfectants that expressed full-length GATA1 were substantially less sensitive to ara-C and gemcitabine than were wild-type and mock-transfected CMK cells, the authors report.
“The results with ara-C and gemcitabine are consistent with the finding of increased cytidine deaminase transcripts in GATA1-transfected cells,” the investigators explain.
Further experiments directly implicated increased cytidine deaminase expression and the increased generation of uridine arabinoside in the GATA1-transfected cells as contributing to decreased generation of ara-C triphosphate.
GATA1 mutations in megakaryoblast samples from Down syndrome children resulted in truncation of the GATA1 protein, the researchers note, and cytidine deaminase transcripts in these megakaryoblasts were 5.1-fold lower than in AML blast cells from non-Down syndrome patients.
Cytidine deaminase transcripts correlated significantly with ara-C sensitivities, the report indicates.
“The findings from our study relate specifically to Down syndrome children with AMkL and suggest that lower doses of chemotherapy drugs including ara-C can be used based on the unique sensitivity of their blast cells to ara-C,” Dr. Taub said. “Using lower doses of drugs could potentially minimize the toxicity of AML therapy in Down syndrome children.”
Source: J Natl Cancer Inst 2005;97:226-231. [ Google search on this article ]
Copyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
