文章：

慢性淋巴细胞白血病的分子发病机制

The molecular pathogenesis of chronic lymphocytic leukaemia

原文发布日期：2016-02-25

DOI: 10.1038/nrc.2016.8

类型: Review Article

开放获取: 否

要点：

1. Chronic lymphocytic leukaemia (CLL), the most common leukaemia in the Western world, is a heterogeneous disease, comprising two main subtypes (known as immunoglobulin heavy chain variable region-mutated (IGHV-M) and IGHV-unmutated (IGHV-UM) CLLs). These subtypes are historically associated with a good and a poor prognosis, respectively, and differ in underlying genetic lesions, degree of genetic clonal evolution, epigenetic changes, activated signalling pathways and microenvironmental interactions.
2. CLL is preceded by an asymptomatic precursor termed monoclonal B cell lymphocytosis (MBL). Traditionally, the two most aggressive clinical types of CLL are those resistant to fludarabine or those transforming to aggressive lymphomas of the diffuse large B cell lymphoma (DLBCL) type, known as Richter syndrome.
3. Although CLL may originate at the haematopoietic stem cell (HSC) stage, the final mature B cell of origin of IGHV-M CLL seems to be a post-GC CD5⁺CD27⁺ B cell, and that of IGHV-UM CLL could be a pre-GC CD5⁺CD27⁻ B cell or a GC-independent memory B cell.
4. B cell receptor (BCR) signalling has an important role in the pathogenesis of CLL, as demonstrated by the presence of a highly restricted and biased repertoire of surface immunoglobulin (sIg) in CLL cells, evidence of autonomous BCR signalling and dramatic clinical responses obtained with BCR pathway inhibitors.
5. The CLL genome displays a relatively low mutational burden and is characterized by a small number of frequently mutated putative 'driver' genes and a large number of rarely altered genes. The CLL epigenome is characterized by widespread hypomethylation of DNA in genes and enhancer loci.
6. A subset of genes mutated in CLL confer a poor outcome in patients with CLL and can improve the classic cytogenetics-based prognostic classification of patients with CLL. Also subclonal high-risk genetic lesions can have a negative impact on the outcome of patients with CLL.
7. Intra-sample genetic and epigenetic heterogeneity are both associated with overall poor survival of patients with CLL.

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，这是一种异质性疾病，包含两种主要亚型（即免疫球蛋白重链可变区突变型[IGHV-M]与未突变型[IGHV-UM]）。这两种亚型历来分别对应良好预后与不良预后，且在基础遗传损伤、遗传克隆进化程度、表观遗传改变、激活的信号通路及微环境相互作用方面存在差异。
2. CLL发病前存在无症状的前驱阶段，称为单克隆B细胞淋巴细胞增多症（MBL）。传统上最具侵袭性的两种CLL临床类型分别是对氟达拉滨耐药的类型，以及转化为弥漫性大B细胞淋巴瘤（DLBCL）的侵袭性淋巴瘤（即Richter综合征）的类型。
3. 虽然CLL可能起源于造血干细胞（HSC）阶段，但IGHV-M型CLL的终末成熟B细胞起源似乎是生发中心后CD5+CD27+B细胞，而IGHV-UM型CLL可能源于生发中心前CD5+CD27−B细胞或生发中心非依赖性记忆B细胞。
4. B细胞受体（BCR）信号在CLL发病机制中具有重要作用，这体现在CLL细胞表面免疫球蛋白（sIg）存在高度受限且偏斜的库、BCR自主信号传导的证据，以及BCR通路抑制剂带来的显著临床应答。
5. CLL基因组突变负荷相对较低，其特征是少量频繁突变的潜在“驱动”基因和大量罕见变异基因。CLL表观基因组的特点是基因和增强子位点存在广泛的DNA低甲基化。
6. CLL中发生突变的部分基因会导致患者预后不良，并可改进基于经典细胞遗传学的CLL患者预后分类。此外，亚克隆性高危遗传损伤也会对CLL患者的预后产生负面影响。
7. 样本内遗传异质性与表观遗传异质性均与CLL患者总体生存率较差相关。

英文摘要：

Recent investigations have provided an increasingly complete picture of the genetic landscape of chronic lymphocytic leukaemia (CLL). These analyses revealed that the CLL genome displays a high degree of heterogeneity between patients and within the same patient. In addition, they highlighted molecular mechanisms and functionally relevant biological programmes that may be important for the pathogenesis and therapeutic targeting of this disease. This Review focuses on recent insights into the understanding of CLL biology, with emphasis on the role of genetic lesions in the initiation and clinical progression of CLL. We also consider the translation of these findings into the development of risk-adapted and targeted therapeutic approaches.

摘要翻译： 

最新研究已逐步勾勒出慢性淋巴细胞白血病（CLL）遗传景观的完整图景。这些分析显示，CLL基因组在不同患者之间以及同一患者内部均表现出高度异质性。此外，研究还揭示了可能对该疾病发病机制和治疗靶点具有重要意义的分子机制及功能相关的生物学程序。本综述聚焦于近期对CLL生物学认知的进展，重点讨论遗传损伤在CLL发生与临床进展中的作用，并探讨如何将这些发现转化为风险适应及靶向治疗策略的开发。

原文链接：

The molecular pathogenesis of chronic lymphocytic leukaemia