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Haploinsufficiency identifies STAT5 as a modifier of IL-7-induced lymphomas

Oncogene volume 24, pages 5252–5257 (2005)Cite this article

Abstract

The requirement for receptor components and the signalling effector, signal transducer and activator of transcription (STAT) 5A/5B, was assessed genetically in a lymphoma development model induced by interleukin-7 (IL-7). This growth factor for T- and B-cell progenitors and mature lymphocytes activates survival and proliferative pathways including Bcl-2, phosphatidylinositol-3 kinase and STAT5. Overexpression of IL-7 in vivo causes early mortality from lymphoma development. Mice overexpressing IL-7 that were heterozygous for the IL-7Rα subunit showed improved survival compared to wild-type mice. In addition, STAT5A/5B+/− compound heterozygous mice with one targeted allele each of STAT5A and STAT5B showed striking amelioration of IL-7-induced mortality and disease development. STAT5A/5B+/− compound heterozygous mice were otherwise normal in stem cell and lymphocyte development and cellularity. Lower STAT5 protein levels accompanied the reduction in STAT5A/5B copy number, which suggests that STAT5 haploinsufficiency is a modifier of IL-7 signal strength.

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Acknowledgements

We thank Nancy Abbey for assistance with histology processing, John Carroll and staff for graphics help. Tg IL-7 mice and STAT5A/5B knockout mice were kindly provided by Dr Benjamin Rich and Dr James Ihle, respectively. NA was supported by a Damon Runyon Cancer Research Foundation Fellowship, DRG-1548. This work was supported by NIH RO1 Grant GM54351 (MAG), and the Canadian Institutes of Health Research (NA).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, The University of British Columbia, #300-6174, University Boulevard, V6 T 1Z3, BC, Canada

    Ninan Abraham & Melissa Jill Miners

  2. Zoology, The University of British Columbia, #300-6174, University Boulevard, V6 T 1Z3, BC, Canada

    Ninan Abraham

  3. Gladstone Institute of Virology and Immunology, San Francisco, 94141, CA, USA

    Ninan Abraham, Melissa C Ma, Jonathan W Snow & Mark A Goldsmith

  4. Department of Microbiology and Immunology, University of California, San Francisco, 94141, CA, USA

    Jonathan W Snow

  5. Department of Pathology, University of California, San Diego, 92103, CA, USA

    Brian G Herndier

  6. Department of Medicine, University of California, San Francisco, 94141, CA, USA

    Mark A Goldsmith

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Correspondence to Ninan Abraham.

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Abraham, N., Ma, M., Snow, J. et al. Haploinsufficiency identifies STAT5 as a modifier of IL-7-induced lymphomas. Oncogene 24, 5252–5257 (2005). https://doi.org/10.1038/sj.onc.1208726

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