The Mer receptor tyrosine is the putative ortholog of the chicken retroviral oncogene, v-eyk, which has been shown to cause several different types of cancer in chickens. Mer, previously cloned and characterized by Dr. Graham, is overexpressed in multiple human cancers and is transforming in vitro. We have specifically been interested in possible oncogenic role of Mer in leukemia and lymphoma. We have found that Mer is not expressed in thymocytes or in lymphocytes, but is ectopically expressed in subsets of patients with both T and B cell acute lymphoblastic leukemia (ALL). Mer activation in these lymphoblasts leads to downstream activation of AKT and ERK 1/2, providing a survival advantage to the cancer cells. We have also made a transgenic mouse in which expression of the full length murine Mer cDNA is under the control of the vav promoter, providing ectopic Mer expression in thymocytes and lymphocytes in a similar manner to the ALL patients. The Mer transgenic mice develop late onset lymphoblastic leukemia and lymphoma which suggests a cooperative role of the Mer in the pathogenesis of leukemia/lymphoma.
Ongoing studies are aimed at Mer inhibition as a novel means of biologically targeted therapy for pediatric leukemia/lymphoma. We also are interested in normal Mer function in macrophages and platelets. Recently, we have found that membrane-bound Mer can be cleaved by a metalloprotease, releasing a truncated and soluble from of Mer (sMer). sMer is abundant in human plasma and acts to bind and sequester the Mer ligand Gas6, thus preventing activation of membrane-bound Mer. The sMer plays an important role in macrophage clearance of apoptotic cells and in platelet function. We are investigating the potential use of sMer as a therapeutic agent in the treatment of patients with clotting disorders.
Keating, A.K., Salzberg, D.B., Sather, S., Liang, X., Nickoloff, S., Anwar, A., DeRyckere, D., Hill, K., Joung, D., Sawczyn, K.K., Park, J., Curran-Everett, D., McGavran, L., Meltesen, L., Gore, L., Johnson, G.L., and D.K. Graham. 2006. Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase, Oncogene, advance online publication 01/05/06 (DOI 10.1038/sj.onc.1209633), e-pub ahead of print.
Graham, D.K., Salzberg, D.B., Kurtzberg, J., Sather, S., Matsushima, G.K., Keating, A.K., Liang, X., Lovell, M.A., Williams, S.A., Dawson, T.L., Schell, M.J., Anwar, A., Snodgrass, H.R., and H.S. Earp. 2006. Ectopic expression of the proto-oncogene Mer in pediatric T cell acute lymphoblastic leukemia, Clinical Cancer Research, 12:2662-2669.
Graham, D.K., Bowman, G.W., Dawson, T.L., Stanford, W.L., Earp, H.S., and H.R. Snodgrass. 1995. Cloning and developmental expression analysis of the murine c-mer tyrosine kinase. Oncogene, 10:2349-2359.
Graham, D.K., Dawson, T.L., Mullaney, D.L., Snodgrass, H.R., and H.S. Earp. 1994. Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. Cell Growth Differ, 5:647-657.
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