Lymphoblastic Leukemia/Lymphoma in Mice Overexpressing the Mer Receptor Tyrosine Kinase.

Abstract

Mer is a transmembrane tyrosine kinase receptor that belongs to a subfamily of tyrosine kinases including Axl and Tyro-3. Within the hematopoietic lineages, Mer is expressed in monocytes/macrophages, dendritic cells and platelets. Normal thymocyte subsets and mature lymphocytes do not express Mer. However, Mer RNA transcript and Mer protein is ectopically expressed in a subset of B cell and T cell acute lymphoblastic leukemia (ALL) cell lines and patient samples. Previous in vitro studies have suggested that constitutive expression of Mer has anti-apoptotic properties and transforming potential. The overexpression of Mer in ALL suggests that this tyrosine receptor kinase may play an important role in leukemogenesis. In an attempt to investigate the oncogenic potential of Mer in vivo, we created a transgenic mouse model in which the expression of the full-length murine Mer cDNA was placed under the control of the Vav promoter. Ectopic expression of Mer has been demonstrated in thymocytes and lymphocytes of the transgenic mice. The ability to activate the ectopic Mer protein with the ligand Gas 6 has confirmed that the protein is functional. Gas 6 stimulation of Mer in lymphocytes from transgenic mice lead to activation of downstream anti-apoptotic signaling pathways including AKT and ERK 1/2. At 12–24 months of age, 60% of the Mer transgenic mice developed lymphadenopathy, hepatosplenomegaly and the presence of circulating lymphoblasts. Histopathological analysis was consistent with a diagnosis of lymphoblastic leukemia/lymphoma. The majority of the lymphomas characterized by flow cytometry were identified as T cell lymphomas with a small subset having co-expression of both T cell and B cell markers. Tumor-free survival in Mer transgenic mice were significantly decreased as compared to the wild type mice (p=0. 003). These data suggest that Mer may play a cooperative role in leukemogenesis and is an attractive candidate marker for biologically targeted leukemia/lymphoma therapy.