Leukemia is a cancer of the bone marrow or blood characterized by aberrant growth of white cells (leukocytes) in the blood and is the most common childhood cancer. Glucocorticoids are a proven class of cancer therapeutic widely used in the treatment of leukemia, and children whose leukemic blasts show in vitro resistance to glucocorticoids have a poorer prognosis than those showing in vitro sensitivity. Our laboratory has previously shown that gene expression patterns differed according to sensitivity or resistance to four classes of chemotherapeutic drugs, including glucocorticoids. MicroRNA (miRNA) is a recently discovered class of small regulatory RNA that controls gene expression. Roughly 21 nucleotides long, these non-coding RNAs are found widely in animals, plants and viruses. MicroRNA expression has already been established in the cytogenetics and prognosis of adult acute myeloid leukemia as well as prognosis and progression in chronic lymphocytic leukemia. In addition particular miRNAs have been shown to function as leukemia-specific tumor suppressors by targeting the BCR-ABL1 fusion protein (Philadelphia chromosome). In pharmacogenomic terms, an miRNA binding-site single-nucleotide polymorphism (miRSNP) in the dihydrofolate reductase gene has been shown to lead to methotrexate resistance in cultured cell lines. Messenger RNA (mRNA) level differences in glucocorticoid-resistant pediatric ALL have been found;however, the role of miRNA in determining transcriptional agendas controlling drug sensitivity in ALL has not been explored. Therefore, the focus of this research proposal will be: 1. To ascertain the functional significance of miRNA in determining glucocorticoid sensitivity or resistance of leukemic cells and 2. To examine the molecular mechanism of miRNA differential expression in drug-sensitive or -resistant leukemia patient populations. We will utilize miRNA-specific microarrays and next-generation sequencing platforms to determine novel and differentially expressed miRNA predictive of glucocorticoid resistance and integrate this knowledge into cell-based measures of glucocorticoid response, genome-wide analysis of copy-number alterations, genotype, and mRNA expression levels.
This proposal seeks to address the role of miRNA in the mechanism of drug resistance of acute lymphoblastic leukemia. We will investigate miRNA as a novel therapeutic target in cancer.
