Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides
Copyright policy )Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides
AbstractAntiapoptotic 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. (Blood. 2005;105:3303-3311)
Cell Survival, Gene Expression Regulation, Leukemic, Fusion Proteins, bcr-abl, Down-Regulation, Antineoplastic Agents, In Vitro Techniques, Oligonucleotides, Antisense, MAP Kinase Kinase Kinases, Milk Proteins, Piperazines, Neoplasm Proteins, DNA-Binding Proteins, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Benzamides, Imatinib Mesylate, Animals, Humans, Myeloid Cell Leukemia Sequence 1 Protein, Extracellular Signal-Regulated MAP Kinases, K562 Cells
Cell Survival, Gene Expression Regulation, Leukemic, Fusion Proteins, bcr-abl, Down-Regulation, Antineoplastic Agents, In Vitro Techniques, Oligonucleotides, Antisense, MAP Kinase Kinase Kinases, Milk Proteins, Piperazines, Neoplasm Proteins, DNA-Binding Proteins, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Benzamides, Imatinib Mesylate, Animals, Humans, Myeloid Cell Leukemia Sequence 1 Protein, Extracellular Signal-Regulated MAP Kinases, K562 Cells
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