Brandão Luis, Migdall-Wilson Justine, Eisenman Kristen, Graham Douglas K
Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.
Crit Rev Oncog. 2011;16(1-2):47-63. doi: 10.1615/critrevoncog.v16.i1-2.60.
In the past 30 years there has been remarkable progress in the treatment of leukemia and lymphoma. However, current treatments are largely ineffective against relapsed leukemia and, in the case of pediatric patients, are often associated with severe long-term toxicities. Thus, there continues to be a critical need for the development of effective biologically targeted therapies. The TAM family of receptor tyrosine kinases-Tyro3, Axl, and Mer-plays an important role in normal hematopoiesis, including natural killer cell maturation, macrophage function, and platelet activation and signaling. Furthermore, TAM receptor activation leads to upregulation of pro-survival and proliferation signaling pathways, and aberrant TAM receptor expression contributes to cancer development, including myeloid and lymphoid leukemia. This review summarizes the role of TAM receptors in leukemia. We outline TAM receptor expression patterns in different forms of leukemia, describe potential mechanisms leading to their overexpression, and delineate the signaling pathways downstream of receptor activation that have been implicated in leukemogenesis. Finally, we discuss the current research focused on inhibitors against these receptors in an effort to develop new therapeutic strategies for leukemia.
在过去30年里，白血病和淋巴瘤的治疗取得了显著进展。然而，目前的治疗方法对复发白血病大多无效，而且对于儿科患者而言，往往伴有严重的长期毒性。因此，仍然迫切需要开发有效的生物靶向疗法。受体酪氨酸激酶TAM家族（Tyro3、Axl和Mer）在正常造血过程中发挥重要作用，包括自然杀伤细胞成熟、巨噬细胞功能以及血小板激活和信号传导。此外，TAM受体激活导致促生存和增殖信号通路上调，TAM受体异常表达促进癌症发展，包括髓系和淋巴系白血病。本综述总结了TAM受体在白血病中的作用。我们概述了TAM受体在不同形式白血病中的表达模式，描述了导致其过表达的潜在机制，并阐述了受体激活下游与白血病发生有关的信号通路。最后，我们讨论了目前针对这些受体抑制剂的研究，以期开发白血病的新治疗策略。
