Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML)

• Published in: Blood 2006-04, Vol.107 (8), p.3279-3287
• Main Authors: Scherr, Michaela, Chaturvedi, Anuhar, Battmer, Karin, Dallmann, Iris, Schultheis, Beate, Ganser, Arnold, Eder, Matthias
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Antigens, CD34 - metabolism; Benzamides; Biological and medical sciences; Combined Modality Therapy - methods; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - metabolism; Gene Expression Regulation, Leukemic - drug effects; Gene Expression Regulation, Leukemic - genetics; Genetic Therapy - methods; Genetic Vectors - genetics; Genetic Vectors - therapeutic use; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; K562 Cells; Lentivirus; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Piperazines - therapeutic use; Protein Kinase Inhibitors - therapeutic use; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Pyrimidines - therapeutic use; RNA Interference; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacology; Signal Transduction - genetics; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-08-3087

Although targeting the BCR-ABL tyrosine kinase activity by imatinib mesylate has rapidly become first-line therapy in chronic myeloid leukemia (CML), drug resistance suggests that combination therapy directed to a complementing target may significantly improve treatment results. To identify such potential targets, we used lentivirus-mediated RNA interference (RNAi) as a tool for functional genomics in cell lines as well as primary normal and CML CD34+ cells. In a conditional cell culture model, we demonstrate that RNAi-mediated reduction of SHP2, STAT5, and Gab2 protein expression inhibits BCR-ABL-dependent but not cytokine-dependent proliferation in a dose-dependent manner. Similarly, colony formation of purified primary CML but not of normal CD34+ colony-forming cells is specifically reduced by inhibition of SHP2, STAT5, and Gab2 expression, respectively. In addition, coexpression of both anti-BCR-ABL and anti-SHP2 shRNAs from a single lentiviral vector induces stronger inhibition of colony formation as compared to either shRNA alone. The data indicate that BCR-ABL expression may affect the function of normal signaling molecules. Targeting these molecules may harbor significant therapeutic potential for the treatment of patients with CML.