文章：

套细胞淋巴瘤的遗传和分子发病机制：新的靶向治疗的观点

Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics

原文发布日期：2007-10-01

DOI: 10.1038/nrc2230

类型: Review Article

开放获取: 否

要点：

1. Mantle cell lymphoma (MCL) is a lymphoid neoplasm characterized by an abnormal proliferation of mature B lymphocytes, which probably derive from naive B cells expressing CD5. This tumour is considered one of the most aggressive lymphoid neoplasms, with poor responses to conventional chemotherapy and relatively short survival. A subset of patients with a more indolent clinical course has been recognized.
2. The genetic hallmark of this neoplasm is the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1, which has an important pathogenetic role, probably deregulating cell cycle control by overcoming the suppressor effect of retinoblastoma 1 (RB1) and the cell cycle inhibitor p27.
3. In addition to this translocation, MCL tumour cells carry a high number of secondary chromosomal and molecular alterations targeting proteins that regulate the cell cycle and senescence (BMI1, INK4a, ARF, CDK4 and RB1) and interfere with the cellular response to DNA damage (ATM, CHK2 and p53).
4. The clinical evolution of patients with MCL is very variable. At present, the quantification of the proliferative activity of the tumour is the best survival predictor, but a more precise evaluation of patient prognosis, through the study of specific chromosomal alterations, may help to design more tailored therapies.
5. New therapeutic strategies that target cell pathways deregulated in these tumours are opening new possibilities for the treatment of patients with MCL. Specifically, compounds that interfere with cell proliferation mechanisms, which actively promote apoptosis or inhibit the survival signals of tumour cells, have provided promising results in preclinical models and preliminary clinical trials. A thorough understanding of the mechanisms of action of these drugs may help to design more rational strategies.

要点翻译：

1. 套细胞淋巴瘤（MCL）是一种以成熟B淋巴细胞异常增殖为特征的淋巴肿瘤，这些细胞可能源自表达CD5的初始B细胞。该肿瘤被视为最具侵袭性的淋巴肿瘤之一，对常规化疗反应较差且患者生存期相对较短。目前已被识别出部分患者具有更温和的临床进程。
2. 该肿瘤的遗传学标志是t(11;14)(q13;q32)易位，导致细胞周期蛋白D1过度表达。这种异常具有重要致病作用，可能通过克服视网膜母细胞瘤蛋白1（RB1）和细胞周期抑制蛋白p27的抑制作用，从而解除细胞周期调控。
3. 除该易位外，MCL肿瘤细胞还携带大量次级染色体和分子异常，涉及调控细胞周期与衰老的蛋白（BMI1、INK4a、ARF、CDK4和RB1），并干扰细胞对DNA损伤的应答机制（ATM、CHK2和p53）。
4. MCL患者的临床进展存在显著差异。目前肿瘤增殖活性的定量评估是最佳生存预测指标，但通过研究特定染色体异常进行更精准的预后评估，有助于制定更个性化的治疗方案。
5. 针对该肿瘤中失调细胞通路的新型治疗策略为MCL患者开辟了新途径。特别是干扰细胞增殖机制、主动促进细胞凋亡或抑制肿瘤细胞存活信号的化合物，在临床前模型和初步临床试验中已展现出良好前景。深入理解这些药物的作用机制，将有助于设计更合理的治疗策略。

英文摘要：

Mantle cell lymphoma (MCL) is a well-defined lymphoid malignancy characterized by a rapid clinical evolution and poor response to current therapeutic protocols. The genetic and molecular mechanisms involved in its pathogenesis combine the dysregulation of cell proliferation and survival pathways with a high level of chromosome instability that seems related to the disruption of the DNA damage response pathway. Understanding these mechanisms and how they affect tumour behaviour is providing the rationale for the identification of reliable predictors of clinical evolution and the design of innovative therapeutic strategies that could open new avenues for the treatment of patients with MCL.

摘要翻译： 

套细胞淋巴瘤（MCL）是一种明确的淋巴系统恶性肿瘤，以临床进展迅速和对现有治疗方案反应差为特征。其发病机制所涉及的遗传和分子机制，既包括细胞增殖与存活通路的失调，也伴随高度染色体不稳定性，后者似乎与DNA损伤应答通路的破坏有关。深入理解这些机制及其对肿瘤行为的影响，正为发现可靠的临床进展预测指标和设计创新治疗策略提供依据，有望为MCL患者的治疗开辟新途径。

原文链接：

Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics