title: Cutting Edge: Codeletion of the Ras GTPase-Activating Proteins (RasGAPs) Neurofibromin 1 and p120 RasGAP in T Cells Results in the Development of T Cell Acute Lymphoblastic Leukemia.
abstract: Ras GTPase-activating proteins (RasGAPs) inhibit signal transduction initiated through the Ras small GTP-binding protein. However, which members of the RasGAP family act as negative regulators of T cell responses is not completely understood. In this study, we investigated potential roles for the RasGAPs RASA1 and neurofibromin 1 (NF1) in T cells through the generation and analysis of T cell-specific RASA1 and NF1 double-deficient mice. In contrast to mice lacking either RasGAP alone in T cells, double-deficient mice developed T cell acute lymphoblastic leukemia/lymphoma, which originated at an early point in T cell development and was dependent on activating mutations in the Notch1 gene. These findings highlight RASA1 and NF1 as cotumor suppressors in the T cell lineage.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Beth A
authors.initials: BA
authors.lastname: Lubeck
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Philip E
authors.initials: PE
authors.lastname: Lapinski
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Oliver
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143;
authors.forename: Olga
authors.initials: O
authors.lastname: Ksionda
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.affiliation: Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, MI 48109; and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Mark
authors.initials: M
authors.lastname: Chiang
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143;
authors.forename: Jeroen
authors.initials: J
authors.lastname: Roose
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; kingp@umich.edu.
authors.forename: Philip D
authors.initials: PD
authors.lastname: King
mesh_terms: D000818:Animals; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D020729:p120 GTPase Activating Protein / Q000172:deficiency / Q000235:genetics* / Q000276:immunology
chemical_list: D025542:Neurofibromin 1; C497762:Notch1 protein, mouse; C581321:RASA1 protein, mouse; D051881:Receptor, Notch1; D020729:p120 GTPase Activating Protein