This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Graham, D. K. Articles by Earp, H. S. Search for Related Content PubMed PubMed Citation Articles by Graham, D. K. Articles by Earp, H. S.

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.

This article has been cited by other articles:

				E. Marston, V. Weston, J. Jesson, E. Maina, C. McConville, A. Agathanggelou, A. Skowronska, K. Mapp, K. Sameith, J. E. Powell, et al. Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response Blood, January 1, 2009; 113(1): 117 - 126. [Abstract] [Full Text] [PDF]

				A. Kazeros, B.-G. Harvey, B. J. Carolan, H. Vanni, A. Krause, and R. G. Crystal Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette Smokers Am. J. Respir. Cell Mol. Biol., December 1, 2008; 39(6): 747 - 757. [Abstract] [Full Text] [PDF]

				B. Burington, B. Barlogie, F. Zhan, J. Crowley, and J. D. Shaughnessy Jr. Tumor Cell Gene Expression Changes Following Short-term In vivo Exposure to Single Agent Chemotherapeutics are Related to Survival in Multiple Myeloma Clin. Cancer Res., August 1, 2008; 14(15): 4821 - 4829. [Abstract] [Full Text] [PDF]

				N. Tibrewal, Y. Wu, V. D'mello, R. Akakura, T. C. George, B. Varnum, and R. B. Birge Autophosphorylation Docking Site Tyr-867 in Mer Receptor Tyrosine Kinase Allows for Dissociation of Multiple Signaling Pathways for Phagocytosis of Apoptotic Cells and Down-modulation of Lipopolysaccharide-inducible NF-{kappa}B Transcriptional Activation J. Biol. Chem., February 8, 2008; 283(6): 3618 - 3627. [Abstract] [Full Text] [PDF]

				S. Sather, K. D. Kenyon, J. B. Lefkowitz, X. Liang, B. C. Varnum, P. M. Henson, and D. K. Graham A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation Blood, February 1, 2007; 109(3): 1026 - 1033. [Abstract] [Full Text] [PDF]