Journal
CELL CYCLE
Volume 9, Issue 6, Pages 1037-1042Publisher
LANDES BIOSCIENCE
DOI: 10.4161/cc.9.6.11011
Keywords
miRNA; processing; mutation; steroid resistance; miR-128
Categories
Funding
- Japan Society for the Promotion of Science
- U.S. National Institutes of Health [R01 DK068348]
- Dutch Cancer Society
- Netherlands Organization for Scientific Research
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MLL-AF4 Acute Lymphocytic Leukemia has a poor prognosis, and the mechanisms by which these leukemias develop are not understood despite intensive research based on well-known concepts and methods. MicroRNAs ( miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate expression of target mRNA transcripts. We recently reported that ectopic expression of miR-128b together with miR-221, two of the miRNAs downregulated in MLL-AF4 ALL, restores glucocorticoid resistance through downregulation of the MLL-AF4 chimeric fusion proteins MLL-AF4 and AF4-MLL that are generated by chromosomal translocation t(4; 11). Here we report the identification of new mutations in miR-128b in RS4; 11 cells, derived from MLL-AF4 ALL patient. One novel mutation significantly reduces the processing of miR-128b. Finally, this base change occurs in a primary MLL-AF4 ALL sample as an acquired mutation. These results demonstrate that the novel mutation in miR-128b in MLL-AF4 ALL alters the processing of miR-128b and that the resultant downregulation of mature miR-128b contributes to glucocorticoid resistance through the failure to downregulate the fusion oncogenes.
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