Herbert Irving Comprehensive Cancer Center, Department of Pathology & Cell Biology, 1130 St. Nicolas Avenue, New York, NY 10032, USA.
Semin Cancer Biol. 2010 Dec;20(6):377-83. doi: 10.1016/j.semcancer.2010.10.012. Epub 2010 Oct 26.
Chronic lymphocytic leukemia (CLL), an incurable disease of the elderly, stands out as unique among the malignancies derived from mature B lymphocytes. The histology, immunophenotype, immunoglobulin variable region (IgV) gene somatic hypermutation status, and the pattern of genetic alterations of the tumor cells are markedly distinct from that of any other B-cell tumor. Most notably, CLL cases can have somatically mutated as well as unmutated IgV genes which largely correlate with a favorable and unfavorable clinical prognosis, respectively. Moreover, recent evidence suggests that 6% of the normal elderly population develops a monoclonal B-cell lymphocytosis (MBL) that appears as the precursor to CLL in 1-2% of cases. Over the last decade, global gene expression profile analysis was instrumental in defining CLL as a malignancy originating from the oncogenic transformation of a common cellular precursor that resembles an antigen-experienced B cell. These findings were complemented by the realization that all CLL, independent of their IgV gene somatic mutation status, express B-cell receptors (BCRs) that show evidence of antigen-experience. Indeed, the BCRs of CLL cases among different individuals can be similar to the extent that one was able to define subsets of stereotyped receptors based on the homology in the antigen-binding regions. Together, these observations strongly support the notion that antigen plays a critical role in CLL pathogenesis. This role is complemented by genetic alterations that, analogous to most cancer types, represent the initiating pathogenetic event. In fact, CLL cases display recurrent genetic aberrations including trisomy 12 and monoallelic or biallelic deletion/inactivation of chromosomal regions 17p, 11q and 13q14. However, virtually all CLL cases lack balanced reciprocal chromosomal translocations, the genetic hallmark of germinal center (GC)-derived lymphomas. The most frequent genetic aberration in CLL, deletion of chromosomal region 13q14, was recently shown to have a specific role in CLL pathogenesis. This region encodes a tumor suppressor locus comprising a microRNA cluster embedded in a long sterile RNA gene, whose deletion in the mouse leads to lymphoproliferative syndromes recapitulating the human CLL-associated spectrum, including MBL, CLL and B-cell non-Hodgkin lymphoma (B-NHL). This review will focus on the cellular origin of CLL, its relationship to the mechanisms of generating CLL-associated genetic lesions and on the role of the 13q14 deletion in CLL pathogenesis as emerging from the analysis of a newly generated mouse model.
慢性淋巴细胞白血病（CLL）是一种无法治愈的老年疾病，它在成熟 B 淋巴细胞来源的恶性肿瘤中具有独特的特征。肿瘤细胞的组织学、免疫表型、免疫球蛋白可变区（IgV）基因体细胞突变状态和遗传改变模式与任何其他 B 细胞肿瘤明显不同。值得注意的是，CLL 病例可以有体细胞突变和未突变的 IgV 基因，这与分别具有有利和不利的临床预后相关。此外，最近的证据表明，6%的正常老年人群发展为单克隆 B 细胞淋巴增生（MBL），在 1-2%的病例中表现为 CLL 的前体。在过去的十年中，全球基因表达谱分析有助于将 CLL 定义为一种起源于常见细胞前体的致癌转化的恶性肿瘤，这种前体类似于抗原经验丰富的 B 细胞。这些发现得到了补充，即所有 CLL 无论其 IgV 基因体细胞突变状态如何，都表达 B 细胞受体（BCR），这些受体显示出抗原经验的证据。事实上，不同个体的 CLL 病例的 BCR 可以相似到可以基于抗原结合区域的同源性来定义定型受体亚群的程度。这些观察结果共同强烈支持抗原在 CLL 发病机制中起关键作用的观点。这种作用与类似于大多数癌症类型的遗传改变相辅相成，遗传改变代表起始的发病事件。事实上，CLL 病例表现出反复的遗传异常，包括 12 号染色体三体和 17p、11q 和 13q14 染色体区域的单等位基因或双等位基因缺失/失活。然而，几乎所有的 CLL 病例都缺乏平衡的相互染色体易位，这是生发中心（GC）衍生淋巴瘤的遗传特征。在 CLL 中最常见的遗传异常，即 13q14 缺失，最近被证明在 CLL 发病机制中具有特定作用。该区域编码一个肿瘤抑制基因座，包括嵌入在长非编码 RNA 基因中的 microRNA 簇，该基因在小鼠中的缺失导致淋巴增生综合征，重现人类 CLL 相关谱，包括 MBL、CLL 和 B 细胞非霍奇金淋巴瘤（B-NHL）。这篇综述将重点讨论 CLL 的细胞起源、它与产生 CLL 相关遗传病变的机制的关系，以及从新生成的小鼠模型分析中得出的 13q14 缺失在 CLL 发病机制中的作用。
