Abstract
Infant acute lymphoblastic leukemia (IALL) is characterized by mixed lineage leukemia (MLL) gene rearrangements, unique gene expression profiles, poor prognosis, and drug resistance. One exception is cytosine arabinoside (Ara-C) to which IALL cells seem to be more sensitive. We quantified mRNA expression of Ara-C key enzymes in leukemic lymphoblasts from 64 Brazilian ALL children, 15 of them presenting MLL gene rearrangement, and correlated it with clinical and biological features. The diagnosis was based on morphological criteria and immunophenotyping using monoclonal antibodies. MLL gene rearrangements were detected by conventional cytogenetic analysis, RT-PCR and/or fluorescence in situ hybridization. The DCK and HENT1 expression levels were determined by real-time quantitative PCR using SYBR Green I. Relative quantification was made by the standard curve method. The results were analyzed by Mann-Whitney and Fisher exact tests. A P value of £0.05 was considered to be statistically significant. DCK and HENT1 expression levels were significantly lower in children with MLL gene-rearranged ALL compared to children with MLL germ line ALL (P = 0.0003 and 0.03, respectively). Our results differ from previous ones concerning HENT1 mRNA expression that observed a higher expression level in MLL gene-rearranged leukemias. In conclusion, the expression of the genes related to Ara-C metabolism was lower in MLL-positive children in the sample studied, suggesting the presence of population differences in the expression profile of these genes especially for HENT1.
Highlights
There is evidence that specific leukemic subgroups may have distinct etiologies, and that molecular abnormalities associated with particular subgroups may be linked to specific causal mechanisms
Infant acute lymphoblastic leukemias (IALLs) display unique biological features and clinical features that provide investigative models and important insights for the study of leukemogenesis [1]
Characterized by mixed lineage leukemia (MLL) gene rearrangements, unique gene expression profiles, and a poor prognosis, infant ALL is usually considered to be a separate subgroup of childhood ALL [1,16,17]
Summary
There is evidence that specific leukemic subgroups may have distinct etiologies, and that molecular abnormalities associated with particular subgroups may be linked to specific causal mechanisms. Infant acute lymphoblastic leukemias (IALLs) display unique biological features (e.g., nearly 80% of infants with leukemia have a leukemic cell abnormality involving the mixed lineage leukemia gene, MLL) and clinical features (e.g., increased rates of treatment failure in infants compared to older children) that provide investigative models and important insights for the study of leukemogenesis [1]. Reported gene expression profiles have shown that ALLs possessing a rearranged MLL gene have a highly uniform and unique pattern that clearly distinguishes them from other ALL subtypes [2,3]. The optimum treatment for patients with MLL gene rearrangements remains to be identified. The very poor outcome of treatment for these patients, especially those diagnosed during infancy, has led to the recommendation of allogeneic hemopoietic stem-cell transplantation [4]. Pieters et al [5] showed in in vitro experiments that leukemic cells from infants with ALL are more resistant to prednisone and L-asparaginase and more sensitive to cytosine arabinoside (Ara-C) than cells from older children with ALL
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