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Dominant action of mutated erythropoietin receptors on differentiation in vitro and erythroleukemia development in vivo

Oncogene volume 19, pages 953–960 (2000)Cite this article

Abstract

J2E cells produce rapid, fatal erythroleukemias in vivo but still respond to erythropoietin (epo) in vitro by differentiating, proliferating and remaining viable in the absence of serum. Mutant epo receptors were introduced into these cells to determine whether they could influence the different biological responses to epo in vitro and the development of erythroleukemias. Three mutant receptors were used as cytoplasmic truncation mutants Δ257 and Δ321 (above box 1 and below box 2 respectively), and the cytoplasmic point mutant W282R (defective for JAK2 activation). Strikingly, the Δ321 mutation produced a hyper-sensitive response in vitro to epo-induced differentiation and viability, but not to proliferation. In contrast with the Δ321 receptor, the Δ257 and W282R mutants inhibited all biological responses to epo due to impaired JAK2 phosphorylation. Significantly, erythroleukemias took almost twice as long to develop with cells containing the W282R mutation, indicating that JAK2 plays an important role in the emergence of these leukemias. These data demonstrate that mutant epo receptors dominantly altered responses of J2E cells to epo in culture and the development of erythroleukemias.

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Acknowledgements

Recombinant human epo (Eprex) was a generous gift from Dr J Adams and Dr J Patava (Janssen-Cilag, Australia). We thank Shane Meakins, Jennifer Beaumont and Ruth Busche for excellent technical assistance. This work was supported by grants from NHMRC (99-0596) and Cancer Foundation of Western Australia (to PA Tilbrook) and grant-in-aid (96G-01616) from the American Heart Association, Texas Affiliate, Inc, Texas Higher Education Co-ordinating Board (ARP 15-120) (to SS Watowich).

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  1. Vanessa Cull and Peta A Tilbrook: V Cull and PA Tilbrook contributed equally to this work

Authors and Affiliations

  1. Department of Biochemistry, Laboratory for Cancer Medicine, University of Western Australia and Royal Perth Hospital, Western Australia, Australia

    Vanessa Cull, Peta A Tilbrook, Aini S Adenan, David Chappell, Evan Ingley, Mohinder K Sarna, T Norman Palmer & S Peter Klinken

  2. Department of Immunology, MD Anderson Cancer Center, Houston, Texas, USA

    Stephanie S Watowich

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Cull, V., Tilbrook, P., Adenan, A. et al. Dominant action of mutated erythropoietin receptors on differentiation in vitro and erythroleukemia development in vivo. Oncogene 19, 953–960 (2000). https://doi.org/10.1038/sj.onc.1203370

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