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.
Division of Molecular Therapy Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Ai
A
Kotani
Daon
D
Ha
Diana
D
Schotte
Monique L
ML
den Boer
Scott A
SA
Armstrong
Harvey F
HF
Lodish
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