title: Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML).
abstract: 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.
authors.affiliation: Medizinische Hochschule Hannover, Zentrum Innere Medizin, Abteilung Hämatologie, Hämostaseologie und Onkologie, Carl-Neuberg Strasse 1, D-30623 Hannover, Germany. m.scherr@t-online.de
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.forename: Anuhar
authors.initials: A
authors.lastname: Chaturvedi
authors.forename: Karin
authors.initials: K
authors.lastname: Battmer
authors.forename: Iris
authors.initials: I
authors.lastname: Dallmann
authors.forename: Beate
authors.initials: B
authors.lastname: Schultheis
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34 / Q000378:metabolism; D001549:Benzamides; D003131:Combined Modality Therapy / Q000379:methods; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D020014:K562 Cells; D016086:Lentivirus; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D001549:Benzamides; C490895:GAB2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases