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Screening for microRNAs in myelodysplastic syndromes

Over the years, evidence has accumulated that microRNAs (miRNAs) play important roles in epigenetic gene regulation. These non-protein coding transcripts are encoded by polycistronic or individual genes which can be in introns of protein encoding genes [1]. Notably, many miRNA encoding genes are in fragile sites in chromosomes or in chromosomal locations involved in cancer-associated deletion or amplification [2]. Mature miRNAs influence protein expression by participating in RNA silencing complexes. A target mRNA which is completely homologous to the miRNA is degraded, while messages with partial homology to the miRNA are not degraded, but their translation is impaired [1]. miRNA expression profiles suggest a functional role in cellular development and carcinogenesis. During hematopoiesis, specific groups of miRNA are associated with discrete differentiation stages of various blood cell lineages [3]. Certain cancerspecific miRNA expression profiles have also been identified and described [4]. For instance, distinct miRNA profiles predict specific forms of lymphoma and chronic lymphocytic leukemia [5,6]. In acute myeloid leukemia (AML), miRNA expression profiles correlate with specific chromosomal translocations or other prognostically significant genetic mutations [7,8], while in chronic myeloid leukemia, miRNA expression profiles identify chronic phase vs. blast crisis [9]. Although there is much information on the expression of distinct miRNAs in different hematologic malignancies, far less is known regarding the functional significance of such miRNAs. In lymphoma, decreased miR-16 may impair apoptosis via Bcl2 targeting [10], while other studies have shown that downregulation of miR-221/222 facilitates erythropoiesis by targeting c-kit in progenitor cells [11]. Studies of the miR-17-92 cluster determined that three members (17-5p, 17-3p, and 18a) target the mRNA for the monocyte colony stimulating factor receptor (M-CSF-R) [12] and increased expression of this cluster is associated with monocytoid blasts in AML [8]. Myelodysplastic syndromes (MDS) are a diverse group of disorders characterized by hematopoietic stem cell (HSC) defects and genomic instability. Early in the course of MDS, apoptosis of bone marrow progenitors predominates and subjects exhibit multi-lineage cytopenias. Accumulation of genetic defects in MDS leads to increased proliferation, differentiation block and progression to secondary AML (sAML). The International Prognostic Scoring System (IPSS) assigns a score to patients with MDS based on the number of lineages involved, percent of bone marrow myeloid blasts, and cytogenetic abnormalities. Although the IPSS permits prediction of prognosis and latency to sAML, mechanistic insights are not derived from this system. In comparison to lymphoma or AML, mRNA expression profiles have been less useful in prognostic grouping of MDS patients. This makes miRNA profiling an intriguing approach to prognosis and a possible window into the pathogenesis of MDS. The study of Pons et al. in this issue of the journal [13] identifies 12 miRNAs which are overexpressed in the bone marrow of subjects with MDS. Six are also overexpressed in peripheral blood cells, three of which are members of the miR-17-92 cluster.