Abstract
Antiapoptotic members of the bcl-2 family have recently been implicated in the pathogenesis of chronic myeloid leukemia (CML), a hematopoietic neoplasm associated with the BCR/ABL oncogene. We have examined expression of MCL-1 in primary CML cells and BCR/ABL-transformed cell lines. Independent of the phase of disease, isolated primary CML cells expressed myeloid cell leukemia-1 (mcl-1) mRNA and the MCL-1 protein in a constitutive manner. The BCR/ABL inhibitor imatinib (=STI571) decreased the expression of MCL-1 in these cells. Correspondingly, BCR/ABL enhanced mcl-1 promoter activity, mcl-1 mRNA expression, and the MCL-1 protein in Ba/F3 cells. BCR/ABL-dependent expression of MCL-1 in Ba/F3 cells was counteracted by the mitogen-activated protein-kinase/extracellular signal-regulated kinase (MEK) inhibitor, PD98059, but not by the phosphoinositide 3-kinase inhibitor, LY294002. Identical results were obtained for constitutive expression of MCL-1 in primary CML cells and the CML-derived cell lines K562 and KU812. To investigate the role of MCL-1 as a survival-related target in CML cells, mcl-1 siRNA and mcl-1 antisense oligonucleotides (ASOs) were applied. The resulting down-regulation of MCL-1 was found to be associated with a substantial decrease in viability of K562 cells. Moreover, the mcl-1 ASO was found to synergize with imatinib in producing growth inhibition in these cells. Together, our data identify MCL-1 as a BCR/ABL-dependent survival factor and interesting target in CML.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / pharmacology*
-
Benzamides
-
Cell Survival / physiology
-
DNA-Binding Proteins / metabolism
-
Down-Regulation
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Fusion Proteins, bcr-abl / genetics
-
Fusion Proteins, bcr-abl / metabolism*
-
Gene Expression Regulation, Leukemic / drug effects
-
Gene Expression Regulation, Leukemic / physiology
-
Humans
-
Imatinib Mesylate
-
In Vitro Techniques
-
K562 Cells
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
-
MAP Kinase Kinase Kinases / metabolism
-
Milk Proteins / metabolism
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism*
-
Oligonucleotides, Antisense / pharmacology*
-
Piperazines / pharmacology*
-
Proto-Oncogene Proteins c-bcl-2 / genetics
-
Proto-Oncogene Proteins c-bcl-2 / metabolism*
-
Pyrimidines / pharmacology*
-
RNA, Small Interfering / pharmacology
-
STAT5 Transcription Factor
-
Trans-Activators / metabolism
-
Tumor Cells, Cultured
-
raf Kinases / metabolism
-
ras Proteins / metabolism
Substances
-
Antineoplastic Agents
-
Benzamides
-
DNA-Binding Proteins
-
Milk Proteins
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Neoplasm Proteins
-
Oligonucleotides, Antisense
-
Piperazines
-
Proto-Oncogene Proteins c-bcl-2
-
Pyrimidines
-
RNA, Small Interfering
-
STAT5 Transcription Factor
-
Trans-Activators
-
Imatinib Mesylate
-
Fusion Proteins, bcr-abl
-
raf Kinases
-
Extracellular Signal-Regulated MAP Kinases
-
MAP Kinase Kinase Kinases
-
ras Proteins