文章：

从慢性淋巴细胞白血病的发病机理到治疗

From pathogenesis to treatment of chronic lymphocytic leukaemia

原文发布日期：2009-12-03

DOI: 10.1038/nrc2764

类型: Review Article

开放获取: 否

要点：

1. Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world. It is characterized by the accumulation of small B lymphocytes that have a mature appearance.
2. Two subsets of CLL cases can be differentiated by the degree of somatic hypermutation (mutated and unmutated immunoglobulin heavy chain variable region (IGHV) genes) that have distinct clinical and biological behaviours.
3. Overall, more than 20% of CLL cases carry stereotyped B cell receptors, suggesting that common antigen(s) are recognized by CLL cells.
4. Clonal B cell populations with a CLL immunophenotype have been detected in 3.5% of healthy individuals (monoclonal B cell lymphocytosis; MBL). MBL is often a CLL precursor.
5. Approximately 80% of CLLs show aberrations in a few frequently affected chromosomal regions, including 13q14 (mir-15a and mir16-1), 11q23 (ataxia telangiectasia-mutated; ATM), trisomy 12 and 17p13 (TP53). Recurrent translocations are rare in CLL.
6. Global and gene-specific aberrant DNA methylation has been detected in CLL. Almost all sporadic CLL cases also show epigenetic silencing of death-associated protein kinase 1.
7. In lymphoid organs, CLL cells interact with and seem to shape their microenvironment, which consists of T cells, stromal cells and soluble factors. This interaction is emerging as a therapeutic target.
8. p53 plays a central part in our current understanding of why some patients fail to respond to chemotherapy.
9. The most powerful prognostic factors include 17p13 deletion, TP53 mutation, 11q23 deletion, IGHV mutation status, serum markers, clinical stage and age.
10. CLL may serve as a model of how microenvironmental stimuli, antigenic drive and epigenetic, as well as genetic, deregulation are combined in cancer pathogenesis.

要点翻译：

1. 慢性淋巴细胞白血病（CLL）是西方世界最常见的白血病类型，其特征为具有成熟外观的小B淋巴细胞异常积聚。
2. 根据体细胞超突变程度（突变与未突变的免疫球蛋白重链可变区基因），CLL可分为两个具有不同临床和生物学行为的亚型。
3. 总体而言，超过20%的CLL病例携带模式化B细胞受体，提示CLL细胞可识别共同抗原。
4. 在3.5%的健康个体中可检测到具有CLL免疫表型的单克隆B细胞群（单克隆B淋巴细胞增多症；MBL），MBL常为CLL的前期病变。
5. 约80%的CLL患者存在少数常见染色体区域异常，包括13q14（mir-15a和mir16-1）、11q23（共济失调毛细血管扩张突变基因）、12号染色体三体及17p13（TP53）。CLL中罕见复发性易位。
6. 研究发现CLL存在全局性和基因特异性DNA甲基化异常。几乎所有散发性CLL病例均表现死亡相关蛋白激酶1的表观遗传沉默。
7. 在淋巴器官中，CLL细胞与由T细胞、基质细胞及可溶性因子构成的微环境相互作用并重塑该环境，这种相互作用正成为新兴治疗靶点。
8. 在当前对化疗耐药机制的理解中，p53发挥着核心作用。
9. 最重要的预后因素包括17p13缺失、TP53突变、11q23缺失、IGHV突变状态、血清标志物、临床分期和年龄。
10. CLL可作为典型范例，展示微环境刺激、抗原驱动、表观遗传及遗传失调在癌症发病机制中如何协同作用。

英文摘要：

Chronic lymphocytic leukaemia (CLL) has several unique features that distinguish it from other cancers. Most CLL tumour cells are inert and arrested in G0/G1 of the cell cycle and there is only a small proliferative compartment; however, the progressive accumulation of malignant cells will ultimately lead to symptomatic disease. Pathogenic mechanisms have been elucidated that involve multiple external (for example, microenvironmental stimuli and antigenic drive) and internal (genetic and epigenetic) events that are crucial in the transformation, progression and evolution of CLL. Our growing understanding of CLL biology is allowing the translation of targets and biological classifiers into clinical practice.

摘要翻译： 

慢性淋巴细胞白血病（CLL）具有与其他癌症不同的几个独特特征。大多数CLL肿瘤细胞处于惰性状态，停滞在细胞周期的G0/G1期，增殖部分很小；然而，恶性细胞的逐渐积累最终将导致有症状的疾病。已经阐明了涉及多种外部（例如，微环境刺激和抗原驱动）和内部（遗传和表观遗传）事件的致病机制，这些机制在CLL的转化、进展和演变中至关重要。我们对CLL生物学的日益了解正在使靶点和生物学分类器转化为临床实践。

原文链接：

From pathogenesis to treatment of chronic lymphocytic leukaemia