miR-128b is a potent glucocorticoid sensitizer in MLL-AF4 acute lymphocytic leukemia cells and exerts cooperative effects with miR-221

Blood. 2009 Nov 5;114(19):4169-78. doi: 10.1182/blood-2008-12-191619. Epub 2009 Sep 11.

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