TY - JOUR
T1 - Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL-rearranged infant acute lymphoblastic leukemia
AU - Stam, Ronald W
AU - Den Boer, Monique L
AU - Schneider, Pauline
AU - de Boer, Jasper
AU - Hagelstein, Jill
AU - Valsecchi, Maria G
AU - de Lorenzo, Paola
AU - Sallan, Stephen E
AU - Brady, Hugh J M
AU - Armstrong, Scott A
AU - Pieters, Rob
PY - 2010/2/4
Y1 - 2010/2/4
N2 - 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.
AB - 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.
KW - Cell Survival/drug effects
KW - Child
KW - Drug Resistance, Neoplasm/genetics
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Leukemic
KW - Gene Rearrangement
KW - Glucocorticoids/pharmacology
KW - Histone-Lysine N-Methyltransferase
KW - Humans
KW - Immunoblotting
KW - Infant
KW - Myeloid Cell Leukemia Sequence 1 Protein
KW - Myeloid-Lymphoid Leukemia Protein/genetics
KW - Oligonucleotide Array Sequence Analysis
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Prednisone/pharmacology
KW - Proto-Oncogene Proteins c-bcl-2/genetics
KW - RNA Interference
KW - Reverse Transcriptase Polymerase Chain Reaction
U2 - 10.1182/blood-2009-02-205963
DO - 10.1182/blood-2009-02-205963
M3 - Article
C2 - 19965632
SN - 0006-4971
VL - 115
SP - 1018
EP - 1025
JO - Blood
JF - Blood
IS - 5
ER -