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, Graham D K
Department of Pediatrics, University of Colorado at Denver and Health Sciences Center, Denver, CO 80045, USA.
Oncogene. 2006 Oct 5;25(45):6092-100. doi: 10.1038/sj.onc.1209633. Epub 2006 May 1.
Mer (MerTK) is a receptor tyrosine kinase important in platelet aggregation, as well as macrophage cytokine secretion and clearance of apoptotic cells. Mer is not normally expressed in thymocytes or lymphocytes; however, ectopic Mer RNA transcript and protein expression is found in a subset of acute lymphoblastic leukemia cell lines and patient samples, suggesting a role in leukemogenesis. To investigate the oncogenic potential of Mer in vivo, we created a transgenic mouse line (Mer(Tg)) that expresses Mer in the hematopoietic lineage under control of the Vav promoter. Ectopic expression and activation of the transgenic Mer protein was demonstrated in lymphocytes and thymocytes of the Mer(Tg) mice. At 12-24 months of age, greater than 55% of the Mer(Tg) mice, compared to 12% of the wild type, developed adenopathy, hepatosplenomegaly, and circulating lymphoblasts. Histopathological analysis and flow cytometry were consistent with T-cell lymphoblastic leukemia/lymphoma. Mer may contribute to leukemogenesis by activation of Akt and ERK1/2 anti-apoptotic signals, which were upregulated in Mer(Tg) mice. Additionally, a significant survival advantage was noted in Mer(Tg) lymphocytes compared to wild-type lymphocytes after dexamethasone treatment. These data suggest that Mer plays a cooperative role in leukemogenesis and may be an effective target for biologically based leukemia/lymphoma therapy.
Mer（MerTK）是一种受体酪氨酸激酶，在血小板聚集、巨噬细胞细胞因子分泌以及凋亡细胞清除过程中发挥重要作用。Mer通常不在胸腺细胞或淋巴细胞中表达；然而，在一部分急性淋巴细胞白血病细胞系和患者样本中发现了异位的Mer RNA转录本和蛋白表达，提示其在白血病发生过程中发挥作用。为了研究Mer在体内的致癌潜力，我们构建了一个转基因小鼠品系（Mer(Tg)），该品系在Vav启动子的控制下在造血谱系中表达Mer。在Mer(Tg)小鼠的淋巴细胞和胸腺细胞中证实了转基因Mer蛋白的异位表达和激活。在12至24月龄时，超过55%的Mer(Tg)小鼠出现了腺病、肝脾肿大和循环淋巴母细胞，而野生型小鼠的这一比例为12%。组织病理学分析和流式细胞术结果与T细胞淋巴母细胞白血病/淋巴瘤相符。Mer可能通过激活Akt和ERK1/2抗凋亡信号促进白血病发生，这些信号在Mer(Tg)小鼠中上调。此外，地塞米松处理后，与野生型淋巴细胞相比，Mer(Tg)淋巴细胞具有显著的生存优势。这些数据表明，Mer在白血病发生过程中发挥协同作用，可能是基于生物学的白血病/淋巴瘤治疗的有效靶点。
