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Increased megakaryocytopoiesis in Lyn-deficient mice

Oncogene volume 25, pages 3316–3324 (2006)Cite this article

Abstract

Previous studies in cell lines have shown Lyn kinase to be a negative regulator of thrombopoietin (TPO)-induced proliferation. To further investigate the role of Lyn during megakaryocytopoiesis, Lyn-deficient mice (lyn−/−) were analyzed. We observed that lyn−/− mice have more bone marrow-derived GPIIB (CD41) and Mpl+ cells when compared to their wild-type littermates. In addition, colony-forming unit-megakaryocytes (CFU-MK) are increased and TPO-induced expansion of primary marrow cells yielded a greater number of mature megakaryocytes (MKs) with increased nuclear ploidy. Histopathology of bone marrow and spleens from lyn−/− mice showed an increase in the number of MKs. Mechanistic studies revealed that TPO stimulation of MKs from lyn−/− mice did not affect phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription (STAT) 3, STAT5, or MAP kinase kinase (MEK). Lyn-deficient MKs supported greater TPO-mediated phosphorylation and kinase activity of both Erk1/2 (mitogen-activated protein kinase, MAPK) and Akt. In contrast, there was a reduction of tyrosine phosphorylation of the inositol phosphatase, SHIP. This is the first direct evidence using primary MKs from Lyn-deficient mice that confirms our prior data from cell lines that Lyn kinase is a negative regulator of TPO signaling.

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Acknowledgements

We thank those individuals who have contributed to this manuscript: Janet Oliver (University of New Mexico) for lyn−/− mice; Jan Johnson (University of Washington) for advice and discussions; Amgen and Zymogenetics for originally providing anti-Mpl antiserum. This work is supported by the National Institutes of Health Grants K01DK065129 and R01HL65498.

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Authors and Affiliations

  1. Puget Sound Blood Center, Seattle, WA, USA

    B J Lannutti, J Minear, N Blake & J G Drachman

  2. Division of Hematology, University of Washington Medical Center, Seattle, WA, USA

    B J Lannutti & J G Drachman

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  1. B J Lannutti
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  2. J Minear
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  3. N Blake
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  4. J G Drachman
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Correspondence to B J Lannutti.

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Lannutti, B., Minear, J., Blake, N. et al. Increased megakaryocytopoiesis in Lyn-deficient mice. Oncogene 25, 3316–3324 (2006). https://doi.org/10.1038/sj.onc.1209351

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