ABSTRACT
OBJECTIVES: Lenalidomide is a potent drug with pleiotropic effects in patients with myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 5 [del(5q)]. We investigated its effect on regulation of microRNA (miRNA) expression profiles in del(5q) patients with MDS in vivo. METHODS: We used miRNA expression microarrays to study changes in miRNA levels in peripheral blood CD14+ monocytes collected from patients before and during lenalidomide treatment and compared them with those from healthy donors. RESULTS: Before treatment, we observed strong upregulation of pro-apoptotic miR-34a and miR-34a* that diminished during lenalidomide exposure. Upregulation of HOX-related miR-196b and erythroid-specific miR-451 seen in untreated patients remained unchanged after the treatment. At the time of hematologic response, expression of several miRNAs clustering to the 14q32 locus was reduced. Additionally, we focused more deeply on miRNAs from the 5q commonly deleted region and found that levels of miR-378 and miR-378* followed haploinsufficiency trend. CONCLUSIONS: This report describes changes in miRNA expression in del(5q) patients with MDS treated with lenalidomide, likely arising from deregulation of pathways implicated in lenalidomide action.
Subject(s)
Anemia, Macrocytic/drug therapy , Gene Expression Regulation, Neoplastic , Immunologic Factors/therapeutic use , MicroRNAs/genetics , Myelodysplastic Syndromes/drug therapy , Thalidomide/analogs & derivatives , Aged , Anemia, Macrocytic/genetics , Anemia, Macrocytic/metabolism , Anemia, Macrocytic/pathology , Case-Control Studies , Chromosome Deletion , Chromosomes, Human, Pair 14 , Chromosomes, Human, Pair 5/genetics , Chromosomes, Human, Pair 5/metabolism , Female , Gene Expression Profiling , Genetic Loci , Genome-Wide Association Study , Haploinsufficiency , Humans , Lenalidomide , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Male , MicroRNAs/metabolism , Middle Aged , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Myelodysplastic Syndromes/pathology , Primary Cell Culture , RNA Splicing , Signal Transduction , Thalidomide/therapeutic useABSTRACT
BACKGROUND: Interactions between genetic variants and risk factors in myelodysplastic syndromes are poorly understood. In this case-control study, we analyzed 1 421 single nucleotide polymorphisms in 408 genes involved in cancer-related pathways in 198 patients and 292 controls. METHODS: The Illumina SNP Cancer Panel was used for genotyping of samples. The chi-squared, p-values, odds ratios and upper and lower limits of the 95% confidence interval were calculated for all the SNPs that passed the quality control filtering. RESULTS: Gene-based analysis showed nine candidate single nucleotide polymorphisms significantly associated with the disease susceptibility (q-value<0.05). Four of these polymorphisms were located in oxidative damage/DNA repair genes (LIG1, RAD52, MSH3 and GPX3), which may play important roles in the pathobiology of myelodysplastic syndromes. Two of nine candidate polymorphisms were located in transmembrane transporters (ABCB1 and SLC4A2), contributing to individual variability in drug responses and patient prognoses. Moreover, the variations in the ROS1 and STK6 genes were associated with the overall survival of patients. CONCLUSIONS: Our association study identified genetic variants in Czech population that may serve as potential markers for myelodysplastic syndromes.
