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

• Published in: Blood Vol. 105; no. 8; pp. 3303 - 3311
• Main Authors: Aichberger, Karl J., Mayerhofer, Matthias, Krauth, Maria-Theresa, Skvara, Hans, Florian, Stefan, Sonneck, Karoline, Akgul, Cahit, Derdak, Sophia, Pickl, Winfried F., Wacheck, Volker, Selzer, Edgar, Monia, Brett P., Moriggl, Richard, Valent, Peter, Sillaber, Christian
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.04.2005; The Americain Society of Hematology
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Benzamides; Biological and medical sciences; Cell Survival - physiology; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); 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; Hematologic and hematopoietic diseases; 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; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; MAP Kinase Kinase Kinases - metabolism; Medical sciences; Milk Proteins - metabolism; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oligonucleotides, Antisense - pharmacology; Pharmacology. Drug treatments; Piperazines - pharmacology; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrimidines - pharmacology; raf Kinases - metabolism; ras Proteins - metabolism; RNA, Small Interfering - pharmacology; STAT5 Transcription Factor; Trans-Activators - metabolism; Tumor Cells, Cultured; Chromosomal aberration; Antineoplastic agent; Synergism; Myeloproliferative syndrome; Abnormal chromosome C9; Chronic myelocytic leukemia; Established cell line; Abnormal chromosome G22; Protein-tyrosine kinase; Hybrid gene; Chromosome translocation; Human; Imatinib; Protein MCL-1; Enzyme; Transferases; Enzyme inhibitor; Malignant hemopathy; Antisense oligonucleotide; Philadelphia chromosome; Chronic; Treatment; Protein kinase; Bcr-abl protein; Abnormal chromosome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-02-0749

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. (Blood. 2005;105:3303-3311)