A novel mutation in the miR-128b gene reduces miRNA processing and leads to glucocorticoid resistance of MLL-AF4 acute lymphocytic leukemia cells.
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.
Kotani
Ai
A
Division of Molecular Therapy Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Ha
Daon
D
Schotte
Diana
D
den Boer
Monique L
ML
Armstrong
Scott A
SA
Lodish
Harvey F
HF
D000483:Alleles; D001483:Base Sequence; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D017354:Point Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects / Q000235:genetics*
D005938:Glucocorticoids; D035683:MicroRNAs; C545189:MIRN128 microRNA, human; C525709:MIR221, human