Reply to Vázquez et al.: MicroRNA deregulation by EVI1 in human and murine malignancies

Abstract

Vazquez et al. (1) analyzed the expression of microRNAs (miRNAs) in cell lines and peripheral blood or bone marrow samples of acute myeloid leukemia (AML) patients. They report that miRNA-124 is down-regulated in those cell lines and primary samples in which the EVI1 oncogene is expressed (1). This is in agreement with what we reported for a murine system (2). Most importantly, however, their work confirms the critical role of miRNAs in maintaining the normal functions of a cell and the versatility of animal systems to evaluate these genes. EVI1 has long been associated with hematopoietic malignancies and aggressive solid tumors. Several investigators have reported on cellular pathways that are disrupted by EVI1, but the early molecular events leading to the deregulation of these pathways remain elusive. Even less is known about the role of EVI1 in a normal or transformed cell. Therefore, the data by Vazquez et al. (1) bring a perspective on the functions of this gene in human leukemia. Over the past few years and especially during the last several months, there has been an accumulation of valuable information on the role of miRNAs in normal and transformed cells (3). We reported that, in the mouse, EVI1 significantly alters at least 15 miRNAs, including miRNA-124. Because of the agreement between the data on miRNA-124 obtained by Vazquez et al. (1) with human samples and our results obtained in the mouse (2), we looked at the other miRNAs that are deregulated by EVI1 in the mouse (Table 1). Thus far, no role has been established in stem cells or leukemia/cancer for four of these genes (N/A in Table 1), whereas an expression deregulation has been found and reported for the remaining genes in either stem cell proliferation (miRNA-125a) or cancer (all of the remaining miRNAs). Remarkably, the up-regulation or silencing of these genes, published by others and indicated by the words Up or Down in Table 1, matches exactly with our findings. At this time, the mechanisms responsible for the alteration of the majority of these miRNAs are not yet known, but it is likely that they include methylation, deletions, amplifications, or mutations involving miRNA loci or epigenetic silencing and deregulation of transcription factors that target specific miRNAs (4). The report by Vazquez et al. (1) and our report confirm the crucial role of DNA methylation in miRNA silencing, confirming growing evidence that aberrant gene expression in cancer is linked to epigenetic deregulation mechanisms such as cytosine methylation in regions of DNA that are rich in cytosine-guanine dinucleotides. (5). The abnormal expression of EVI1 is often associated with malignancies that are characterized by frequent epigenetic abnormalities, including the methylation of a gene's regulatory region. Taken together, our results and the work by Vazquez et al. (1) suggest a strong causal link between EVI1 and inappropriate gene methylation, provide insights into a possible cause of inappropriate DNA methylation, and open alternative avenues for the development of therapeutic strategies.