Peirs Sofie, Van der Meulen Joni, Van de Walle Inge, Taghon Tom, Speleman Frank, Poppe Bruce, Van Vlierberghe Pieter
Center for Medical Genetics, Ghent University, Ghent, Belgium.
Immunol Rev. 2015 Jan;263(1):50-67. doi: 10.1111/imr.12237.
Normal T-cell development is a strictly regulated process in which hematopoietic progenitor cells migrate from the bone marrow to the thymus and differentiate from early T-cell progenitors toward mature and functional T cells. During this maturation process, cooperation between a variety of oncogenes and tumor suppressors can drive immature thymocytes into uncontrolled clonal expansion and cause T-cell acute lymphoblastic leukemia (T-ALL). Despite improved insights in T-ALL disease biology and comprehensive characterization of its genetic landscape, clinical care remained largely similar over the past decades and still consists of high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable side effects, clinical outcome is still extremely poor in a significant subset of T-ALL patients as a result of therapy resistance or hematological relapses. Recent genetic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in T-ALL, suggesting that epigenetic homeostasis is critically required in restraining tumor development in the T-cell lineage. In this review, we provide an overview of the epigenetic regulators that could be implicated in T-ALL disease biology and speculate how the epigenetic landscape of T-ALL could trigger the development of epigenetic-based therapies to further improve the treatment of human T-ALL.
正常T细胞发育是一个严格调控的过程，在此过程中造血祖细胞从骨髓迁移至胸腺，并从早期T细胞祖细胞分化为成熟且有功能的T细胞。在这个成熟过程中，多种癌基因与肿瘤抑制因子之间的协同作用可驱使未成熟胸腺细胞进行不受控制的克隆性扩增，进而引发T细胞急性淋巴细胞白血病（T-ALL）。尽管对T-ALL疾病生物学的认识有所增进，其遗传图谱也得到了全面表征，但在过去几十年里临床治疗基本保持不变，仍包括大剂量多药化疗，之后可能进行造血干细胞移植。即便采用这种往往伴有相当多副作用的积极治疗方案，由于治疗耐药或血液学复发，相当一部分T-ALL患者的临床结局依然极差。最近的遗传学研究已确定T-ALL中参与DNA甲基化和翻译后组蛋白修饰的基因存在反复的体细胞改变，这表明表观遗传稳态对于抑制T细胞谱系中的肿瘤发展至关重要。在本综述中，我们概述了可能与T-ALL疾病生物学相关的表观遗传调节因子，并推测T-ALL的表观遗传图谱如何能够推动基于表观遗传学的疗法的开发，以进一步改善人类T-ALL的治疗。
