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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

Beth A. Lubeck, Philip E. Lapinski, Jennifer A. Oliver, Olga Ksionda, Luis F. Parada, Yuan Zhu, Ivan Maillard, Mark Chiang, Jeroen Roose and Philip D. King
J Immunol July 1, 2015, 195 (1) 31-35; DOI: https://doi.org/10.4049/jimmunol.1402639
Beth A. Lubeck
*Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
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Philip E. Lapinski
*Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
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Jennifer A. Oliver
*Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
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Olga Ksionda
†Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143;
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Luis F. Parada
‡Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
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Yuan Zhu
§Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, MI 48109; and
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Ivan Maillard
¶Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
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Mark Chiang
¶Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
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Jeroen Roose
†Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143;
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Philip D. King
*Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
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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.

Footnotes

  • This work was supported by National Institutes of Health Grants R01 HL096498 and T32 AI007431.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    DKO
    double knockout
    DN
    double-negative
    DP
    double-positive
    ICN
    intracellular Notch
    NF1
    neurofibromin 1
    qPCR
    quantitative PCR
    RASA1
    p120 Ras GTPase-activating protein
    RasGAP
    Ras GTPase-activating protein
    T-ALL
    T cell acute lymphoblastic leukemia/lymphoma.

  • Received October 17, 2014.
  • Accepted April 28, 2015.
  • Copyright © 2015 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 195 (1)
The Journal of Immunology
Vol. 195, Issue 1
1 Jul 2015
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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
Beth A. Lubeck, Philip E. Lapinski, Jennifer A. Oliver, Olga Ksionda, Luis F. Parada, Yuan Zhu, Ivan Maillard, Mark Chiang, Jeroen Roose, Philip D. King
The Journal of Immunology July 1, 2015, 195 (1) 31-35; DOI: 10.4049/jimmunol.1402639

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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
Beth A. Lubeck, Philip E. Lapinski, Jennifer A. Oliver, Olga Ksionda, Luis F. Parada, Yuan Zhu, Ivan Maillard, Mark Chiang, Jeroen Roose, Philip D. King
The Journal of Immunology July 1, 2015, 195 (1) 31-35; DOI: 10.4049/jimmunol.1402639
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