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Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a
D J P M Stumpel1, D Schotte, E A M Lange-Turenhout
1Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
Abstract:
MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is the most aggressive type of childhood leukemia. To develop more suitable treatment strategies, a firm understanding of the biology underlying this disease is of utmost importance. MLL-rearranged ALL displays a unique gene expression profile, partly explained by erroneous histone modifications. We recently showed that t(4;11)-positive infant ALL is also characterized by pronounced promoter CpG hypermethylation. In this study, we investigated whether this widespread hypermethylation also affected microRNA (miRNA) expression. We identified 11 miRNAs that were downregulated in t(4;11)-positive infant ALL as a consequence of CpG hypermethylation. Seven of these miRNAs were re-activated after exposure to the de-methylating agent Zebularine. Interestingly, five of these miRNAs are associated either with MLL or MLL fusions, and for miR-152 we found both MLL and DNA methyltransferase 1 (DNMT1) as potential targeted genes. Finally, a high degree of methylation of the miR-152 CpG island was strongly correlated with a poor clinical outcome. Our data suggests that inhibitors of methylation have a potential beyond re-expression of hypermethylated protein-coding genes in t(4;11)-positive infant ALL. In this study, we provide additional evidence that they should be tested for their efficacy in MLL-rearranged infant ALL in in vivo models.
Insights
Infant MLL-rearranged acute lymphoblastic leukemia (ALL) shows hypermethylation affecting microRNA (miRNA) expression. Demethylating agents may offer new therapeutic strategies for this aggressive childhood cancer.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- MLL-rearranged infant acute lymphoblastic leukemia (ALL) is highly aggressive.
- This leukemia subtype exhibits unique gene expression and histone modification patterns.
- Previous work identified promoter CpG hypermethylation in t(4;11)-positive infant ALL.
Purpose of the Study:
- To investigate the impact of CpG hypermethylation on microRNA (miRNA) expression in infant ALL.
- To identify specific miRNAs affected by hypermethylation in t(4;11)-positive ALL.
- To explore the therapeutic potential of demethylating agents in MLL-rearranged infant ALL.
Main Methods:
- Analysis of miRNA expression in t(4;11)-positive infant ALL samples.
- Treatment with the demethylating agent Zebularine to assess miRNA re-activation.
- Identification of potential target genes for affected miRNAs, including miR-152.
- Correlation analysis between miR-152 CpG island methylation and clinical outcome.
Main Results:
- Eleven miRNAs were found to be downregulated due to CpG hypermethylation in t(4;11)-positive infant ALL.
- Seven of these downregulated miRNAs were re-activated by Zebularine treatment.
- Five re-activated miRNAs are linked to MLL or MLL fusions; miR-152 targets MLL and DNMT1.
- High miR-152 CpG island methylation correlated with poor clinical outcome.
Conclusions:
- CpG hypermethylation significantly impacts miRNA expression in MLL-rearranged infant ALL.
- Demethylating agents show promise for re-activating silenced miRNAs in this leukemia.
- Targeting methylation pathways may offer novel therapeutic strategies beyond protein-coding gene re-expression.
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