1. ¹Department of Pediatrics, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA
2. ²Department of Pathology, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA
3. ³Division of Biostatistics, National Jewish Medical and Research Center, Denver, CO, USA
4. ⁴Departments of Preventive Medicine and Biometrics and of Physiology and Biophysics, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA
5. ⁵Colorado Cytogenetics, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA
6. ⁶Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA

Correspondence: Dr DK Graham, Department of Pediatrics, University of Colorado at Denver Health Sciences Center, Pediatrics, Mail Stop 8302, Building RC-1 North, PO Box 6511, 12800 E. 19th Avenue, Aurora, CO 80045, USA. E-mail: doug.graham@uchsc.edu

⁷These authors contributed equally to this manuscript.

Received 9 February 2006; Revised 17 March 2006; Accepted 17 March 2006; Published online 1 May 2006.

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 (Mer_Tg) 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 Mer_Tg mice. At 12–24 months of age, greater than 55% of the Mer_Tg 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 Mer_Tg mice. Additionally, a significant survival advantage was noted in Mer_Tg 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.