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

Abstract

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.Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. The current 80% 5-year event-free survival rate is a product of national pediatric oncology cooperative group clinical trials that have optimized patient outcome. Future improvements will rely on a better understanding of the definition and pathogenesis of different ALL subtypes. Specifically, biologically targeted therapy against unique leukemia markers or signaling pathways is being tested in clinical trials and hopefully will complement current treatment regimens. In this study, we report a new potential biological marker in pediatric ALL.Mer was initially cloned by our group from a human B lymphoblastoid cDNA library, and Mer RNA transcript was also found to be expressed in T-cell ALL (T-ALL) cell lines (1). This was intriguing because Mer RNA was not detected in freshly isolated human (or mouse) T or B lymphocytes. Subsequent work has shown that Mer signaling, via activated Mer receptor tyrosine kinase domain, can be antiapoptotic (32D cells; ref.2), cytoskeletal regulatory, or frankly transforming [Ba/F3 pro-Blymphocytes (3) and NIH 3T3 fibroblasts (4)], depending on the cell type. The retrovirally transduced chicken orthologue v-eyk was also frankly transforming (5, 6). We now show that Mer expression is abs...

Immunobiology of the TAM receptors

“…In addition to the roles discussed in this Review, TAM receptor signalling has been shown have important regulatory roles in vascular smooth-muscle homeostasis [92][93][94] , in platelet function and thrombus stabilization 23,95,96 , in erythropoiesis 97 and in cancer development and progression 19,98,99 . TAM receptors are also implicated in the regulation of osteoclast function 100,101 , in the control of oligodendrocyte cell survival 102,103 , and in the infection of dendritic cells and other cells by Ebola and Marburg viruses 104,105 .…”

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

“…However, the pattern differs for each family member, e.g. Mer is found in lymphoid leukemia while Axl is not (Graham et al, , 2006Neubauer et al, 1994).…”

“…Mer is not expressed in normal mouse or human lymphocytes but is ectopically expressed in T-cell leukemias and E2A-PBX1 positive B-cell leukemias (Graham et al, 2006;Yeoh et al, 2002). To further investigate the oncogenic potential and causal role of Mer in malignancy, our lab developed a Mer transgenic (Mer Tg ) mouse model .…”

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