miR-128b is a potent glucocorticoid sensitizer in MLL-AF4 acute lymphocytic leukemia cells and exerts cooperative effects with miR-221.
MLL-AF4 acute lymphocytic leukemia (ALL) has a poor prognosis. MicroRNAs (miRNA) are small noncoding RNAs that posttranscriptionally regulate expression of target mRNAs. Our analysis of previously published data showed that expression of miR-128b and miR-221 is down-regulated in MLL-rearranged ALL relative to other types of ALL. Reexpression of these miRNAs cooperatively sensitizes 2 cultured lines of MLL-AF4 ALL cells to glucocorticoids. Target genes down-regulated by miR-128b include MLL, AF4, and both MLL-AF4 and AF4-MLL fusion genes; miR-221 down-regulates CDKN1B. These results demonstrate that down-regulation of miR-128b and miR-221 is implicated in glucocorticoid resistance and that restoration of their levels is a potentially promising therapeutic in MLL-AF4 ALL.
Kotani
Ai
A
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Ha
Daon
D
Hsieh
James
J
Rao
Prakash K
PK
Schotte
Diana
D
den Boer
Monique L
ML
Armstrong
Scott A
SA
Lodish
Harvey F
HF
D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D050760:Cyclin-Dependent Kinase Inhibitor p27; D003907:Dexamethasone; D005938:Glucocorticoids; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion; D012334:RNA, Neoplasm; C436291:CDKN1B protein, human; C545189:MIRN128 microRNA, human; C525709:MIR221, human; C113855:MLL-AF4 fusion protein, human