GATA1 mutations in patients with down syndrome and acute megakaryoblastic leukaemia do not always confer a good prognosis

Abstract

Children with Down syndrome and acute megakaryoblastic leukemia (DS-AMKL) have been shown to have increased sensitivity to cytarabine based chemotherapy. The excellent prognosis in patients with DS-AMKL may be due to mutations in the GATA1 gene leading to reduced expression of the enzyme cytidine deaminase. This leads to a decreased ability to convert cytarabine into its inactive metabolite, resulting in high intracellular concentration of this cytotoxic agent. We report two cases of DS-AMKL with GATA1 mutations who had poor outcome. These patients had high expression levels of cytidine deaminase mRNA transcripts. We speculate that other factors can affect overall outcome in patients with DS-AMKL irrespective of the presence of GATA1 mutations.

GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder

“…It was found that CDA mRNA was upregulated in these two patients and was 40-fold higher compared to that of the other ML-DS cases, suggesting greater capability to metabolise ara-C. CDA mRNA expression in these two patients was, however, still lower than that in non-DS AML patients. (20) Therefore, in the presence of GATA1 mutations, CDA gene expression may be heterogeneous. Apart from the CDA gene, GATA1 mutations may be associated with changes in the transactivational activity of many genes that influence treatment response.…”