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Ectopic Expression of the Proto-oncogene Mer in Pediatric T-Cell Acute Lymphoblastic Leukemia

Authors' Affiliations: Departments of ¹ Pediatrics and ² Pathology, University of Colorado Health Sciences Center, Denver, Colorado; ³ Department of Pediatrics, Duke University Medical Center, Durham, North Carolina; ⁴ Department of Microbiology and Immunology and University of North Carolina Neuroscience Center and ⁵ University of North Carolina Lineberger Comprehensive Cancer Center, and Departments of Medicine and Pharmacology, University of North Carolina, Chapel Hill, North Carolina; and ⁶ VistaGen Therapeutics, Inc., Burlingame, California

Requests for reprints: Douglas K. Graham, Department of Pediatrics, University of Colorado Health Sciences Center at Fitzsimons, Mail Stop 8302, PO Box 6511, Aurora, CO 80045. Phone: 303-724-4006; Fax: 303-724-4015; E-mail: doug.graham{at}uchsc.edu.

Purpose: The Mer receptor tyrosine kinase, cloned from a B-lymphoblastoid library, is the mammalian orthologue of the chicken retroviral oncogene v-eyk and sends antiapoptotic and transforming signals when activated. To determine if Mer expression is ectopic in T-cell acute lymphoblastic leukemia (ALL) and potentially important in leukemogenesis, we analyzed Mer expression in normal human thymocytes and lymphocytes and in pediatric ALL patient samples.

Experimental Design: Reverse transcription-PCR, flow cytometry, and immunohistochemistry were used to determine expression of Mer in sorted human thymocyte populations, lymphocytes, and lymphocytes activated by phytohemagglutinin or phorbol 12-myristate 13-acetate/ionophore. Mer expression in 34 T-cell ALL (T-ALL) patient samples was evaluated by reverse transcription-PCR, and Mer protein expression in a separate cohort of 16 patient samples was assayed by flow cytometry and Western blot.

Results: Mer expression was absent in normal thymocytes or lymphocytes, and in T cells activated with phytohemagglutinin or phorbol 12-myristate 13-acetate/ionophore. In contrast, Jurkat cells and T-ALL patient samples expressed unique 180 to 185 kDa Mer protein glycoforms. Substantial Mer RNA levels were principally observed in a subset of T-ALL patient samples that expressed B220 (P = 0.004) but lacked surface expression of CD3 (P = 0.02) and CD4 (P = 0.006), a phenotypic profile consistent with immature lymphoblasts. In addition, 8 of 16 T-ALL patient samples had Mer protein detected by flow cytometry and Western blot.

Conclusions: Transforming Mer signals may contribute to T-cell leukemogenesis, and abnormal Mer expression may be a novel therapeutic target in pediatric ALL therapy.

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