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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA141762-01
Application #
7745844
Study Section
Special Emphasis Panel (ZRG1-F09-B (20))
Program Officer
Jakowlew, Sonia B
Project Start
2009-09-21
Project End
2012-09-20
Budget Start
2009-09-21
Budget End
2010-09-20
Support Year
1
Fiscal Year
2009
Total Cost
$50,054
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Paugh, Steven W; Coss, David R; Bao, Ju et al. (2016) MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression. PLoS Comput Biol 12:e1004744
Paugh, Steven W; Bonten, Erik J; Savic, Daniel et al. (2015) NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nat Genet 47:607-14
Roberts, Kathryn G; Li, Yongjin; Payne-Turner, Debbie et al. (2014) Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 371:1005-15
Jones, Courtney L; Bhatla, Teena; Blum, Roy et al. (2014) Loss of TBL1XR1 disrupts glucocorticoid receptor recruitment to chromatin and results in glucocorticoid resistance in a B-lymphoblastic leukemia model. J Biol Chem 289:20502-15
Panetta, John C; Paugh, Steven W; Evans, William E (2013) Mathematical modeling of folate metabolism. Wiley Interdiscip Rev Syst Biol Med 5:603-13
Paugh, S W; Stocco, G; McCorkle, J R et al. (2011) Cancer pharmacogenomics. Clin Pharmacol Ther 90:461-6
Chen, S-H; Yang, W; Fan, Y et al. (2011) A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity. Leukemia 25:66-74
Paugh, Steven W; Stocco, Gabriele; Evans, William E (2010) Pharmacogenomics in pediatric leukemia. Curr Opin Pediatr 22:703-10
Pottier, N; Paugh, S W; Ding, C et al. (2010) Promoter polymorphisms in the ?-2 adrenergic receptor are associated with drug-induced gene expression changes and response in acute lymphoblastic leukemia. Clin Pharmacol Ther 88:854-61