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Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase

Oncogene volume 25, pages 6092–6100 (2006)Cite this article

Abstract

Mer (MerTK) is a receptor tyrosine kinase important in platelet aggregation, as well as macrophage cytokine secretion and clearance of apoptotic cells. Mer is not normally expressed in thymocytes or lymphocytes; however, ectopic Mer RNA transcript and protein expression is found in a subset of acute lymphoblastic leukemia cell lines and patient samples, suggesting a role in leukemogenesis. To investigate the oncogenic potential of Mer in vivo, we created a transgenic mouse line (MerTg) that expresses Mer in the hematopoietic lineage under control of the Vav promoter. Ectopic expression and activation of the transgenic Mer protein was demonstrated in lymphocytes and thymocytes of the MerTg mice. At 12–24 months of age, greater than 55% of the MerTg mice, compared to 12% of the wild type, developed adenopathy, hepatosplenomegaly, and circulating lymphoblasts. Histopathological analysis and flow cytometry were consistent with T-cell lymphoblastic leukemia/lymphoma. Mer may contribute to leukemogenesis by activation of Akt and ERK1/2 anti-apoptotic signals, which were upregulated in MerTg mice. Additionally, a significant survival advantage was noted in MerTg lymphocytes compared to wild-type lymphocytes after dexamethasone treatment. These data suggest that Mer plays a cooperative role in leukemogenesis and may be an effective target for biologically based leukemia/lymphoma therapy.

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Acknowledgements

We acknowledge Karen Helm and the University of Colorado Flow Cytometry Core for their expertise and assistance. Grant support: DBS is supported by the Schow Research Fellowship from the National Childhood Cancer Foundation. DBS and AKK are supported by the NIH training grant T32CA86068604. DKG is supported by the V Foundation for Cancer Research and The Children's Hospital Research Institute (Denver, CO).

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Author notes

  1. A K Keating and D B Salzberg: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Pediatrics, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA

    A K Keating, D B Salzberg, S Sather, S Nickoloff, A Anwar, D DeRyckere, K Hill, D Joung, K K Sawczyn, J Park, L Gore & D K Graham

  2. Department of Pathology, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA

    X Liang

  3. Division of Biostatistics, National Jewish Medical and Research Center, Denver, CO, USA

    D Curran-Everett

  4. Departments of Preventive Medicine and Biometrics and of Physiology and Biophysics, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA

    D Curran-Everett

  5. Colorado Cytogenetics, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA

    L McGavran & L Meltesen

  6. Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA

    G L Johnson

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Correspondence to D K Graham.

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Keating, A., Salzberg, D., Sather, S. et al. Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase. Oncogene 25, 6092–6100 (2006). https://doi.org/10.1038/sj.onc.1209633

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