Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL-rearranged infant acute lymphoblastic leukemia

Ronald W Stam, Monique L Den Boer, Pauline Schneider, Jasper de Boer, Jill Hagelstein, Maria G Valsecchi, Paola de Lorenzo, Stephen E Sallan, Hugh J M Brady, Scott A Armstrong, Rob Pieters

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

MLL-rearranged acute lymphoblastic leukemia (ALL) represents an unfavorable type of leukemia that often is highly resistant to glucocorticoids such as prednisone and dexamethasone. Because response to prednisone largely determines clinical outcome of pediatric patients with ALL, overcoming resistance to this drug may be an important step toward improving prognosis. Here, we show how gene expression profiling identifies high-level MCL-1 expression to be associated with prednisolone resistance in MLL-rearranged infant ALL, as well as in more favorable types of childhood ALL. To validate this observation, we determined MCL-1 expression with quantitative reverse transcription-polymerase chain reaction in a cohort of MLL-rearranged infant ALL and pediatric noninfant ALL samples and confirmed that high-level MCL-1 expression is associated with prednisolone resistance in vitro. In addition, MCL-1 expression appeared to be significantly higher in MLL-rearranged infant patients who showed a poor response to prednisone in vivo compared with prednisone good responders. Finally, down-regulation of MCL-1 in prednisolone-resistant MLL-rearranged leukemia cells by RNA interference, to some extent, led to prednisolone sensitization. Collectively, our findings suggest a potential role for MCL-1 in glucocorticoid resistance in MLL-rearranged infant ALL, but at the same time strongly imply that high-level MCL-1 expression is not the sole mechanism providing resistance to these drugs.

Original languageEnglish
Pages (from-to)1018-25
Number of pages8
JournalBlood
Volume115
Issue number5
DOIs
Publication statusPublished - 4 Feb 2010
Externally publishedYes

Keywords

  • Cell Survival/drug effects
  • Child
  • Drug Resistance, Neoplasm/genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Gene Rearrangement
  • Glucocorticoids/pharmacology
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Immunoblotting
  • Infant
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Myeloid-Lymphoid Leukemia Protein/genetics
  • Oligonucleotide Array Sequence Analysis
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
  • Prednisone/pharmacology
  • Proto-Oncogene Proteins c-bcl-2/genetics
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction

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