Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Binding Sites / genetics
-
Cell Line, Tumor
-
Cyclin-Dependent Kinase Inhibitor p27
-
Dexamethasone / pharmacology
-
Down-Regulation
-
Drug Resistance, Neoplasm / genetics
-
Gene Expression
-
Glucocorticoids / pharmacology
-
Humans
-
Intracellular Signaling Peptides and Proteins / genetics
-
MicroRNAs / genetics*
-
MicroRNAs / metabolism*
-
Myeloid-Lymphoid Leukemia Protein / genetics*
-
Oncogene Proteins, Fusion / genetics*
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
-
RNA, Neoplasm / genetics*
-
RNA, Neoplasm / metabolism*
-
Transfection
Substances
-
CDKN1B protein, human
-
Glucocorticoids
-
Intracellular Signaling Peptides and Proteins
-
MIRN128 microRNA, human
-
MIRN221 microRNA, human
-
MLL-AF4 fusion protein, human
-
MicroRNAs
-
Oncogene Proteins, Fusion
-
RNA, Neoplasm
-
Cyclin-Dependent Kinase Inhibitor p27
-
Myeloid-Lymphoid Leukemia Protein
-
Dexamethasone