Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale

Abstract

MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (o1 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.

MicroRNAs in acute leukemia: from biological players to clinical contributors

“…Their hypermethylation-related reduced expression levels are therefore specific for MLL-rearranged ALL. The degree of methylation of miR-152 was also predictive for a poor clinical outcome of MLLrearranged ALL, 79 which points to the potential of de-methylating drugs as new therapeutic agents to treat this type of pediatric ALL.…”

“…This is illustrated for miR-152 in Figure 3 (adapted from Stumpel/Schotte et al 79 ). The silencing by DNA methylation suggests that miR-152 and the other six miRNAs (that is, miR-200b, miR-200a, miR-429, miR-503, miR-432 and miR-10a) have tumor suppressive capacities similar to miR124a.…”

“…Accordingly, miR-432 is part of the large miR-127 tumor suppressor cluster that downregulates protein levels of BCL-6. 79 In addition, re-expression of miR-200b coincided with downregulation of the oncogene ZEB2, which is highly expressed in t(4;11)/AF4-MLL-positive ALL 79,83 and led to disease progression in human cancer. 84 MLL wild-type, AF4-MLL and DNMT1 were identified as potential target genes for miR-152 based on 3 0 UTR sequence homology.…”

“…84 MLL wild-type, AF4-MLL and DNMT1 were identified as potential target genes for miR-152 based on 3 0 UTR sequence homology. 79 This is of high interest because the co-expression of MLL wild-type is facilitating MLL-AF9-induced leukemogenesis 85 and the AF4-MLL reciprocal fusion protein contributes to leukemic transformation. 86 Moreover high levels of DNMT1 may be responsible for the genome-wide hypermethylation that characterizes t(4;11)/AF4-MLL-positive ALL and was linked to an increased risk of relapse.…”

“…78 Recently, we proposed that miR-152 may be another actor of the epigenetic machinery because the seed sequence of miR-152 shared sequence homology with the 3 0 UTR of the DNMT1 transcript and expression levels of miR-152 inversely correlated to those of DNMT1 in MLL-rearranged ALL. 79 Others have added miR-290 to this list of so-called 'epi-miRNAs' upon the finding that miR-290 controlled DNA methylation and telomere recombination through retinoblastoma-like 2-dependent regulation of DNMTs. 80 Interestingly, a recent report demonstrated the discovery of a new class of miRNAs that directly (independent of target genes) mediated DNA methylation in plants.…”