title: Grb10 is involved in BCR-ABL-positive leukemia in mice.
abstract: The SH2-containing adaptor protein Grb10 was first identified in a yeast screen as a new binding partner for BCR-ABL and associates with BCR-ABL in a tyrosine-dependent manner. However, its function in BCR-ABL-mediated leukemogenesis in vivo is still unknown. Here we describe an important role of Grb10 in BCR-ABL-induced leukemia by using a versatile system for efficient oncogene expression and simultaneous Grb10 knockdown from a single vector. Primary bone marrow (BM) cells coexpressing Grb10-miR/BCR-ABL showed a significant decrease in colony formation and cell cycle progression. Transplantation of Grb10miR/BCR-ABL- or control-miR/BCR-ABL- transduced BM leads to a CML/B-ALL-like phenotype with significantly delayed disease onset and progression resulting in prolonged overall survival in Grb10-miR-transplanted mice. Methylcellulose experiments exhibit additive effects of imatinib treatment and Grb10 knockdown. Cell cycle analysis suggests an anti-proliferative effect of Grb10 knockdown in BCR-ABL(+) primary BM cells. However, Grb10 abrogation was not capable of completely abolishing the BCR-ABL-induced disease. Our findings were confirmed in the human BCR-ABL(+) cell line K562, where we demonstrate reduced viability, cell cycle progression and induction of apoptosis by stable Grb10 microRNA expression. Taken together, our results suggest that Grb10 knockdown in vivo leads to impaired proliferation, longer survival and reduced colony formation, suggesting an important role of Grb10 in BCR-ABL-mediated leukemogenesis.
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: A L
authors.initials: AL
authors.lastname: Illert
authors.affiliation: 1] Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany [2] Department of Internal Medicine III, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Albers
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kreutmair
authors.affiliation: 1] Department of Internal Medicine III, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany [2] Department of Hematology, Oncology, and Tumor Immunology, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Leischner
authors.affiliation: Department of Internal Medicine III, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Peschel
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Miething
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Duyster
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D051383:GRB10 Adaptor Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D061251:Primary Cell Culture; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C495959:Grb10 protein, mouse; D035683:MicroRNAs; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; C406060:abl-bcr fusion protein, human; D051383:GRB10 Adaptor Protein; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl