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Chronic lymphocytic leukaemia: from genetics to treatment
慢性淋巴细胞白血病:从遗传学到治疗

Francesc Bosch 1 , 2 , 3 1 , 2 , 3 ^(1,2,3**){ }^{1,2,3 *} and Riccardo Dalla-Favera 3 3 ^(3){ }^{3}
Francesc Bosch 1 , 2 , 3 1 , 2 , 3 ^(1,2,3**){ }^{1,2,3 *} 和 Riccardo Dalla-Favera 3 3 ^(3){ }^{3}

Abstract  抽象

Chronic lymphocytic leukaemia (CLL), the most frequent type of leukaemia in adults, is a lymphoproliferative disorder that is characterized by the expansion of monoclonal, mature CD 5 + CD + 3 + B CD 5 + CD + 3 + B CD5^(+)CD^(+)3^(+)B\mathrm{CD5}^{+} \mathrm{CD}^{+} 3^{+} \mathrm{B} cells in the peripheral blood, secondary lymphoid tissues and bone marrow. CLL is an incurable disease with a heterogeneous clinical course, for which the treatment decision still relies on conventional parameters (such as clinical stage and lymphocyte doubling time). During the past 5 years, relevant advances have been made in understanding CLL biology. Indeed, substantial progress has been made in the identification of the putative cell of origin of CLL, and comprehensive studies have dissected the genomic, epigenomic and transcriptomic landscape of CLL. Advances in clinical management include improvements in our understanding of the prognostic value of different genetic lesions, particularly those associated with chemoresistance and progression to highly aggressive forms of CLL, and the advent of new therapies targeting crucial biological pathways. In this Review, we discuss new insights into the genetic lesions involved in the pathogenesis of CLL and how these genetic insights influence clinical management and the development of new therapeutic strategies for this disease.
慢性淋巴细胞白血病 (CLL) 是成人最常见的白血病类型,是一种淋巴组织增生性疾病,其特征是外周血、次级淋巴组织和骨髓中单克隆成熟 CD 5 + CD + 3 + B CD 5 + CD + 3 + B CD5^(+)CD^(+)3^(+)B\mathrm{CD5}^{+} \mathrm{CD}^{+} 3^{+} \mathrm{B} 细胞的扩增。CLL 是一种临床病程异质性的不治之症,其治疗决策仍然依赖于常规参数 (例如临床分期和淋巴细胞倍增时间)。在过去的 5 年中,在理解 CLL 生物学方面取得了相关进展。事实上,在鉴定 CLL 的推定起源细胞方面已经取得了实质性进展,并且全面的研究已经剖析了 CLL 的基因组、表观基因组和转录组景观。临床管理的进步包括提高我们对不同遗传病变预后价值的理解,特别是那些与化疗耐药和进展为高度侵袭性 CLL 相关的病变,以及针对关键生物途径的新疗法的出现。在本综述中,我们讨论了对 CLL 发病机制中涉及的遗传损伤的新见解,以及这些遗传见解如何影响临床管理和该疾病新治疗策略的开发。

1 1 ^(1){ }^{1} Department of Haematology, University Hospital Vall d’Hebron, Autonomous University, Barcelona, Spain.
1 1 ^(1){ }^{1} 西班牙巴塞罗那自治大学 Vall d'Hebron 大学医院血液学系。

2 2 ^(2){ }^{2} Laboratory of Experimental Haematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain.
2 2 ^(2){ }^{2} 西班牙巴塞罗那 Vall d'Hebron 肿瘤研究所 (VHIO) 实验血液学实验室。

3 3 ^(3){ }^{3} Institute for Cancer Genetics, Columbia University, New York, NY, USA.
3 3 ^(3){ }^{3} 哥伦比亚大学癌症遗传学研究所,美国纽约州纽约市。

*e-mail: fbosch@vhio.net
*电子邮件:fbosch@vhio.net

https://doi.org/10.1038/ s41571-019-0239-8
With an estimated incidence of 4.7 new cases per 100,000 individuals, chronic lymphocytic leukaemia (CLL) is the most common form of chronic leukaemia in the USA and in Europe 1 1 ^(1){ }^{1}. In 2017, the estimated number of newly diagnosed cases was 20,110, representing 1.2 % 1.2 % ∼1.2%\sim 1.2 \% of all cancers in the USA 2 2 ^(2){ }^{2}. By contrast, the incidence of CLL among individuals from African, Caribbean and Asian countries is 1.4 1.4 ∼1.4\sim 1.4 new cases per 100,000 individuals, suggesting that genetic factors have a role in this racial disparity 3 , 4 3 , 4 ^(3,4){ }^{3,4}. Accordingly, relatives of patients with CLL have a higher risk of developing CLL and other lymphoproliferative disorders than the general population, although the basis for this genetic susceptibility remains elusive 5 7 5 7 ^(5-7){ }^{5-7}. The median age at diagnosis is 70 years, with a male predominance (1.3:1) in all ethnic subgroups 2 , 8 2 , 8 ^(2,8){ }^{2,8}. As life expectancy and the use of blood testing increase, the prevalence of CLL and the proportion of asymptomatic patients diagnosed with early stage disease will continue to increase, whereas the median age at diagnosis will decrease 2 , 8 2 , 8 ^(2,8){ }^{2,8}.
慢性淋巴细胞白血病 (CLL) 的估计发病率为每 100,000 人 4.7 例,是美国和欧洲 1 1 ^(1){ }^{1} 最常见的慢性白血病形式。2017 年,估计新诊断病例数为 20,110 例,占 1.2 % 1.2 % ∼1.2%\sim 1.2 \% 美国 2 2 ^(2){ }^{2} 所有癌症的病例数。相比之下,非洲、加勒比和亚洲国家个体的 CLL 发病率为 1.4 1.4 ∼1.4\sim 1.4 每 100,000 人中的新病例,这表明遗传因素在这种种族差异中起作用 3 , 4 3 , 4 ^(3,4){ }^{3,4} 。因此,CLL 患者的亲属患 CLL 和其他淋巴组织增生性疾病的风险高于一般人群,尽管这种遗传易感性的基础仍然难以 5 7 5 7 ^(5-7){ }^{5-7} 捉摸。诊断时的中位年龄为 70 岁,在所有种族亚组中 2 , 8 2 , 8 ^(2,8){ }^{2,8} 男性占主导地位 (1.3:1)。随着预期寿命和血液检测使用的增加,CLL 的患病率和被诊断为早期疾病的无症状患者的比例将继续增加,而诊断时的中位年龄将下降 2 , 8 2 , 8 ^(2,8){ }^{2,8}
CLL is a chronic lymphoproliferative disorder 9 , 10 9 , 10 ^(9,10){ }^{9,10} diagnosed by the presence of 5 , 000 5 , 000 >= 5,000\geq 5,000 clonal CD 5 + CD 23 + CD 5 + CD 23 + CD5^(+)CD23^(+)\mathrm{CD5}^{+} \mathrm{CD} 23^{+} B lymphocytes per microlitre of peripheral blood for more than 3 months, or by the presence of its non-leukaemic variant, small lymphocytic lymphoma (SLL) 9 , 10 9 , 10 ^(9,10){ }^{9,10}. CLL remains an incurable disease with a heterogeneous clinical course, for which prognostication is based on simple and highly reproducible clinical parameters that were used to develop two clinical staging systems 11 , 12 11 , 12 ^(11,12){ }^{11,12}.
CLL 是一种慢性淋巴组织增生性疾病, 9 , 10 9 , 10 ^(9,10){ }^{9,10} 诊断为每微升外周血中存在 5 , 000 5 , 000 >= 5,000\geq 5,000 克隆性 CD 5 + CD 23 + CD 5 + CD 23 + CD5^(+)CD23^(+)\mathrm{CD5}^{+} \mathrm{CD} 23^{+} B 淋巴细胞超过 3 个月,或存在其非白血病变异型小淋巴细胞淋巴瘤 (SLL)。 9 , 10 9 , 10 ^(9,10){ }^{9,10} CLL 仍然是一种临床病程异质性的不治之症,其预后基于简单且高度可重复的临床参数,这些参数用于开发两个临床分期系统 11 , 12 11 , 12 ^(11,12){ }^{11,12}
The modified Rai classification, which was derived from the original Rai staging system with five risk subgroups (stages 0-IV) 13 13 ^(13){ }^{13}, defines patients with low-risk CLL who solely display lymphocytosis, intermediate-risk disease with palpable lymph nodes or hepatosplenomegaly, and high-risk disease with anaemia (haemoglobin < 110 g / l < 110 g / l < 110g//l<110 \mathrm{~g} / \mathrm{l} ) or thrombocytopenia (platelet count < 100 × 10 9 / I 13 < 100 × 10 9 / I 13 < 100 xx10^(9)//I^(13)<100 \times 10^{9} / \mathrm{I}^{13}. The Binet classification (Binet A-C) relies on similar physical examination and laboratory findings 12 12 ^(12){ }^{12}. On the basis of the enormous advances in the biology and treatment of CLL, these historical staging systems have been complemented by a plethora of new prognostic and predictive parameters based on CLL genetics and biology for the purpose of predicting patient outcomes and response to treatment 14 17 14 17 ^(14-17){ }^{14-17}.
改良的 Rai 分类源自原始的 Rai 分期系统,具有五个风险亚组(0-IV 期), 13 13 ^(13){ }^{13} 定义了仅表现淋巴细胞增多的低危 CLL 患者、可触及淋巴结或肝脾肿大的中危疾病,以及贫血(血红蛋白 < 110 g / l < 110 g / l < 110g//l<110 \mathrm{~g} / \mathrm{l} )或血小板减少症(血小板计数 < 100 × 10 9 / I 13 < 100 × 10 9 / I 13 < 100 xx10^(9)//I^(13)<100 \times 10^{9} / \mathrm{I}^{13} .Binet 分类 (Binet A-C) 依赖于相似的体格检查和实验室检查结果 12 12 ^(12){ }^{12} 。在 CLL 生物学和治疗的巨大进步的基础上,这些历史分期系统已经得到了大量基于 CLL 遗传学和生物学的新预后和预测参数的补充,以预测患者的预后和对治疗 14 17 14 17 ^(14-17){ }^{14-17} 的反应。
In this Review, we focus on insights into the genetic lesions involved in the pathogenesis of CLL gained over the past 7 years, referring readers to other reviews on the role of the tumour microenvironment 18 18 ^(18){ }^{18}. We discuss the genetic lesions in CLL and their value as both prognostic indicators of clinical course and as predictive biomarkers of response to chemotherapy and targeted therapies.
在这篇综述中,我们重点介绍了过去 7 年中获得的与 CLL 发病机制有关的遗传损伤的见解,并推荐读者参考其他关于肿瘤微环境 18 18 ^(18){ }^{18} 作用的综述。我们讨论了 CLL 的遗传病变及其作为临床病程预后指标以及作为化疗和靶向治疗反应的预测生物标志物的价值。

Genetics and pathogenesis of CLL
CLL 的遗传学和发病机制

Emerging knowledge of CLL genetics and biology indicates that CLL is not a homogeneous disease, informing the current understanding of the distinct cell types from which this malignancy can originate and the complex set of genetic lesions that are associated with its pathogenesis.
CLL 遗传学和生物学的新知识表明 CLL 不是一种同质性疾病,这为当前对这种恶性肿瘤可能起源的不同细胞类型以及与其发病机制相关的复杂遗传病变集的理解提供了信息。

Key points  要点

  • Next-generation sequencing of the coding genome has identified the most common somatic genetic alterations associated with the pathogenesis of chronic lymphocytic leukaemia (CLL).
    编码基因组的下一代测序已经确定了与慢性淋巴细胞白血病 (CLL) 发病机制相关的最常见的体细胞遗传改变。
  • Specific genetic alterations provide biomarkers for prognostication of the clinical course and prediction of response to chemotherapy and targeted therapy.
    特异性基因改变为临床病程的预后和对化疗和靶向治疗的反应预测提供了生物标志物。
  • Recurrent genetic alterations identify cellular pathways that present potential therapeutic targets.
    复发性基因改变确定了呈现潜在治疗靶点的细胞通路。
  • This new knowledge is informing novel treatment algorithms for the clinical management of patients with CLL.
    这些新知识为 CLL 患者临床管理的新治疗算法提供了信息。

Cell of origin  原点细胞

The identification of the cell of origin of any given malignancy (that is, the non-maligant cell from which the malignant transformation originated) can be useful as a reference to identify the alterations in the cell that caused its malignant transformation. Over the years, several cell types have been proposed as putative cells of origin (also sometimes referred to as the ‘normal counterpart’) of CLL on the basis of progressive increases in the understanding of B cell biology and differentiation.
鉴定任何给定恶性肿瘤的起源细胞(即恶性转化起源的非恶意细胞)可用作识别导致其恶性转化的细胞改变的参考。多年来,基于对 B 细胞生物学和分化的理解的逐渐增加,几种细胞类型被提议作为 CLL 的推定起源细胞(有时也称为“正常对应物”)。
The observed presence of clonal rearrangements of immunoglobulin ( I G I G IGI G ) genes along with expression of specific cell surface markers has established that CLL is derived from a mature B cell that is characterized by weak expression of B cell markers (surface membrane immunoglobulins (Ig), CD19 and CD20) and is positive for expression of CD23 (also known as FceRII; a B cell and dendritic cell marker) and of the CD200 and CD5 antigens 10 10 ^(10){ }^{10}. The expression of CD5 led to the hypothesis that CLL is derived from IgM-secreting B1 lineage of B cells that are contributors to innate immunity 19 , 20 19 , 20 ^(19,20){ }^{19,20}, as opposed to the B2 lineage, which is involved in adaptive immunity. Subsequently, the discovery that two subgroups of patients with CLL can be distinguished on the basis of the presence or absence of mutations in the immunoglobulin heavy chain variable region ( I G H V I G H V IGHVI G H V ) genes, which encode part of the B B BB cell receptor (BCR), unequivocally indicated that the IGHV-mutated (IGHV-M) CLLs are derived from antigen-experienced B cells that have transited through the germinal centre (GC) of secondary lymphoid organs, the site of immunoglobulin somatic hypermutation 21 21 ^(21){ }^{21}. Conversely, whether the I G H V I G H V IGHVI G H V-unmutated (IGHV-UM) CLLs are derived from pre-GC (naive) B B BB cells or GC-independent antigen-experienced B B BB cells remains unclear 21 21 ^(21){ }^{21}.
观察到免疫球蛋白 ( I G I G IGI G ) 基因克隆重排的存在以及特定细胞表面标志物的表达已经确定 CLL 来源于成熟 B 细胞,其特征是 B 细胞标志物(表面膜免疫球蛋白 (Ig)、CD19 和 CD20)的弱表达,并且 CD23(也称为 FceRII;B 细胞和树突状细胞标志物)以及 CD200 和 CD5 抗原 10 10 ^(10){ }^{10} 的表达呈阳性.CD5 的表达导致 CLL 来源于分泌 IgM 的 B 细胞 B1 谱系,这些谱系是先天免疫的贡献者 19 , 20 19 , 20 ^(19,20){ }^{19,20} ,而不是参与适应性免疫的 B2 谱系。随后,发现可以根据编码 B B BB 部分细胞受体 (BCR) 的免疫球蛋白重链可变区 ( I G H V I G H V IGHVI G H V ) 基因是否存在突变来区分两个 CLL 患者亚组,这明确表明 IGHV 突变 (IGHV-M) CLL 来源于抗原经历的 B 细胞,这些 B 细胞已经通过次级淋巴器官的生发中心 (GC), 免疫球蛋白体细胞超突变的部位 21 21 ^(21){ }^{21} 。相反,未突变 (IGHV-UM) CLL 是 I G H V I G H V IGHVI G H V 来源于 GC 前(幼稚) B B BB 细胞还是 GC 非依赖性抗原经历 B B BB 的细胞仍不清楚 21 21 ^(21){ }^{21}
Comparative gene expression profiling of CLL specimens and subsets of non-transformed human B B BB cell has shown that both IGHV-M and IGHV-UM subtypes are similar to CD27 + + ^(+){ }^{+}memory B cells 21 21 ^(21){ }^{21}, suggesting that both CLL subtypes originate from antigen-experienced CD27 + + ^(+){ }^{+} B cells, with I G H V I G H V IGHVI G H V-M and I G H V I G H V IGHVI G H V-UM subtypes having been derived from post-GC or GC-independent cells, respectively 21 , 22 21 , 22 ^(21,22){ }^{21,22}. In 2012, transcriptome analyses of subsets of non-transformed B cells suggested that IGHV-M CLLs are derived from a previously unrecognized CD27 + + ^(+){ }^{+}CD5 + + ^(+){ }^{+}post-GC subset, whereas IGVH-UM CLLs resemble CD + CD 27 CD + CD 27 CD^(+)CD27^(-)\mathrm{CD}^{+} \mathrm{CD} 27^{-}IGHV-UM-naive B cells 23 23 ^(23){ }^{23} (FIG. 1).
CLL 标本和非转化人类 B B BB 细胞亚群的比较基因表达谱表明,IGHV-M 和 IGHV-UM 亚型与 CD27 + + ^(+){ }^{+} 记忆 B 细胞 21 21 ^(21){ }^{21} 相似,表明两种 CLL 亚型都起源于抗原经历的 CD27 + + ^(+){ }^{+} B 细胞,其中 I G H V I G H V IGHVI G H V -M 和 I G H V I G H V IGHVI G H V -UM 亚型分别 21 , 22 21 , 22 ^(21,22){ }^{21,22} 来源于 GC 后或不依赖 GC 的细胞.2012 年,对未转化 B 细胞亚群的转录组分析表明,IGHV-M CLL 来源于先前未识别的 CD27 + + ^(+){ }^{+} CD5 + + ^(+){ }^{+} GC 后亚群,而 IVH-UM CLL 类似于 CD + CD 27 CD + CD 27 CD^(+)CD27^(-)\mathrm{CD}^{+} \mathrm{CD} 27^{-} IGHV-UM 幼稚 B 细胞 23 23 ^(23){ }^{23} (图 1)。
A 2012 study comparing the epigenetic profiles of patients with CLL showed that the degree of genome
2012 年的一项比较 CLL 患者表观遗传图谱的研究显示,基因组

methylation in CLL cells is generally similar to that in memory B cells, although CLL-associated differences might reflect the existence of a currently unknown non-malignant B cell subpopulation 24 24 ^(24){ }^{24}. Overall, the distinction between IGHV-M CLL putatively derived from GC-experienced B cells and IGHV-UM CLL arising from pre-GC-naive B cells or GC-independent memory B B BB cells still remains a valid, although not universally accepted, model.
CLL 细胞中的甲基化通常与记忆 B 细胞中的甲基化相似,尽管 CLL 相关差异可能反映了当前未知的非恶性 B 细胞亚群 24 24 ^(24){ }^{24} 的存在。总体而言,推定来源于经历 GC 的 B 细胞的 IGHV-M CLL 与源自 GC 初治前 B 细胞或不依赖 GC 的记忆 B B BB 细胞的 IGHV-UM CLL 之间的区别仍然是一个有效的模型,尽管尚未被普遍接受。
Patients with IGHV-M CLL and those with IGHVUM CLL have a highly restricted repertoire of I G I G IGI G genes, suggesting a role for antigen selection in the pathogenesis of the disease 25 , 26 25 , 26 ^(25,26){ }^{25,26}. Approximately one-third of patients with CLL, particularly those with IGHV-UM CLL, exhibit stereotypic BCRs, which are based on their complementary-determining regions 26 , 27 26 , 27 ^(26,27){ }^{26,27}. To date, >200 different CLL stereotype subsets have been identified 25 25 ^(25){ }^{25}, which can be further subdivided into several subsets with distinct biological and clinical features 28 28 ^(28){ }^{28} : IGHV-UM CLLs tend to express low-affinity, polyreactive and self-reactive BCRs, whereas IGHV-M CLLs usually express oligo-reactive and mono-reactive BCRs 25 25 ^(25){ }^{25}. Notably, both IGHV-M and IGHV-UM subtypes might also rely on antigen-independent, cellautonomous BCR signalling, providing a potential rationale for the therapeutic targeting of the BCR signalling pathway 29 29 ^(29){ }^{29}.
IGHV-M CLL 患者和 IGHVUM CLL 患者的 I G I G IGI G 基因库高度受限,表明抗原选择在疾病 25 , 26 25 , 26 ^(25,26){ }^{25,26} 的发病机制中的作用。大约三分之一的 CLL 患者,尤其是 IGHV-UM CLL 患者,表现出刻板型 BCR,这是基于其互补决定区域 26 , 27 26 , 27 ^(26,27){ }^{26,27} 。迄今为止,已经确定了 25 25 ^(25){ }^{25} >200 种不同的 CLL 刻板型亚群,可以进一步细分为几个具有不同生物学和临床特征 28 28 ^(28){ }^{28} 的亚群:IGHV-UM CLL 倾向于表达低亲和力、多反应性和自反应性 BCR,而 IGHV-M CLL 通常表达寡反应性和单反应性 BCR 25 25 ^(25){ }^{25} .值得注意的是,IGHV-M 和 IGHV-UM 亚型也可能依赖于抗原非依赖性、细胞自主的 BCR 信号传导,为 BCR 信号通路 29 29 ^(29){ }^{29} 的治疗靶向提供了潜在的基本原理。
Finally, the very early genetic and epigenetic events that eventually lead to CLL have been suggested to occur in haematopoietic stem cells (HSCs) 30 30 ^(30){ }^{30}. Consistent with this notion, in some patients with allogeneic HSC transplantation (HSCT), pre-malignant lymphoid cells were transmitted from the donor to the recipient and eventually led to CLL development 30 30 ^(30){ }^{30}. In addition, HSCs from patients with CLL, but not those from healthy donors, have been shown to engraft in immunodeficient mice and induce B cell lymphoproliferations in vivo 31 31 ^(31){ }^{31}. Finally, specific lesions in genes implicated in lymphoid tumours (for example, NOTCH1, SF3B1 and EGR) have been found in purified HSCs from some patients with CLL 32 CLL 32 CLL^(32)\mathrm{CLL}^{32}. Overall, the conclusion that the initial genetic lesions favouring CLL development might occur in HSCs remains controversial, particularly considering the difficulties in purifying CLL-free HSC populations from bone marrow 32 , 33 32 , 33 ^(32,33){ }^{32,33}, and the emerging evidence that healthy elderly individuals have clonal haematopoiesis, which can increase the risk of haematological malignancies, including CLL 34 , 35 34 , 35 ^(34,35){ }^{34,35}, and is associated with subsets of genetic lesions also detected in CLL.
最后,最终导致 CLL 的非常早期的遗传和表观遗传事件被认为发生在造血干细胞 (HSC) 30 30 ^(30){ }^{30} 中。与这一概念一致,在一些同种异体 HSC 移植 (HSCT) 患者中,癌前淋巴细胞从供体传递到受体,并最终导致 CLL 的发展 30 30 ^(30){ }^{30} 。此外,来自 CLL 患者的 HSC,而不是来自健康供体的 HSC,已被证明可以移植到免疫缺陷小鼠体内并在体内 31 31 ^(31){ }^{31} 诱导 B 细胞淋巴增生。最后,在一些 CLL 32 CLL 32 CLL^(32)\mathrm{CLL}^{32} .总体而言,有利于 CLL 发展的初始遗传损伤可能发生在 HSC 中的结论仍然存在争议,特别是考虑到从骨髓中纯化无 CLL 的 HSC 群体的困难 32 , 33 32 , 33 ^(32,33){ }^{32,33} ,以及健康老年人具有克隆造血的新证据,这会增加血液系统恶性肿瘤的风险,包括 CLL 34 , 35 34 , 35 ^(34,35){ }^{34,35} ,并且与在 CLL 中也检测到的遗传病变亚群有关。
Overall, the cell of origin of CLL is a subject of continued debate, with regard to both the cell type in which the first genetic lesion occurs (HSCs versus mature B cells) and to the mature B cell type (pre-GC, post-GC or GC-independent) from which the clonal expansion of overt CLL can originate.
总体而言,CLL 的起源细胞是一个持续争论的话题,涉及发生第一个遗传损伤的细胞类型(HSC 与成熟 B 细胞)和成熟 B 细胞类型(GC 前、GC 后或 GC 非依赖性),显性 CLL 的克隆扩增可能源自。

Recurrent genetic lesions
复发性遗传病变

The development of genome-wide sequencing and copy-number analysis has enabled the thorough characterization of the genomic landscape of CLL (FIG. 2). Whole-exome sequencing (WES) of > 1 , 000 > 1 , 000 > 1,000>1,000 CLL specimens and whole-genome sequencing (WGS) of
全基因组测序和拷贝数分析的发展使得对 CLL 基因组景观的全面表征成为可能(图 2)。CLL 标本的 > 1 , 000 > 1 , 000 > 1,000>1,000 全外显子组测序 (WES) 和

Fig. 1 | The cellular origin of chronic lymphocytic leukaemia. The genetic and epigenetic events leading to chronic lymphocytic leukaemia (CLL) have been suggested to occur in haematopoietic stem cells (HSCs) 31 31 ^(31){ }^{31}, although this hypothesis remains controversial 32 , 33 32 , 33 ^(32,33){ }^{32,33}. After HSCs acquire genetic and epigenetic lesions (indicated by lightning symbols), the nature of which are still unknown, the cellular output of these lesions could be a polyclonal expansion of B cell progenitors. Subsequent antigenic stimulation might lead to oligoclonal selection and expansion of mature B cells. CLL cells with mutations in the immunoglobulin heavy chain variable region genes (IGHV-M) seem to originate from post-germinal centre (GC) CD5 + + ^(+){ }^{+}CD27 + + ^(+){ }^{+}B cells, which are most likely derived from CD 5 + CD 27 + B CD 5 + CD 27 + B CD5^(+)CD27^(+)B\mathrm{CD5}^{+} \mathrm{CD} 27^{+} \mathrm{B} cells that have undergone the GC reaction 23 23 ^(23){ }^{23}. Conversely, IGHV-unmutated (IGHV-UM) CLL seems to be derived from pre-GC CD5 + + ^(+){ }^{+}CD27- B cells, which might arise from naive B B BB cells or from a separate lineage of precursor B B BB cells, probably in a T T TT cell-independent process 23 23 ^(23){ }^{23}. The evolution from these progenitors to monoclonal B lymphocytosis (MBL) and, ultimately, to overt CLL is dictated by additional genetic and epigenetic abnormalities (indicated by lightning symbols), B cell receptor (BCR) stimulation, microenvironmental factors and T cells. The dashed arrows indicate a hypothetical mechanism. TD, T cell-dependent antigen; TI, T cell-independent antigen. Figure adapted from REF. 48 48 ^(48){ }^{48}, Springer Nature Limited.
图 1 |慢性淋巴细胞白血病的细胞起源。导致慢性淋巴细胞白血病 (CLL) 的遗传和表观遗传事件被认为发生在造血干细胞 (HSC) 31 31 ^(31){ }^{31} 中,尽管这一假设仍然存在争议 32 , 33 32 , 33 ^(32,33){ }^{32,33} 。在 HSC 获得遗传和表观遗传病变(由闪电符号表示)后,其性质仍然未知,这些病变的细胞输出可能是 B 细胞祖细胞的多克隆扩增。随后的抗原刺激可能导致成熟 B 细胞的寡克隆选择和扩增。免疫球蛋白重链可变区基因 (IGHV-M) 突变的 CLL 细胞似乎起源于生发中心 (GC) CD5 + + ^(+){ }^{+} CD27 + + ^(+){ }^{+} B 细胞,这些细胞很可能来自 CD 5 + CD 27 + B CD 5 + CD 27 + B CD5^(+)CD27^(+)B\mathrm{CD5}^{+} \mathrm{CD} 27^{+} \mathrm{B} 经历过 GC 反应 23 23 ^(23){ }^{23} 的细胞。相反,IGHV 未突变 (IGHV-UM) CLL 似乎来源于前 GC CD5 + + ^(+){ }^{+} CD27-B 细胞,这可能来自幼稚 B B BB 细胞或前体 B B BB 细胞的单独谱系,可能处于 T T TT 细胞非依赖性过程中 23 23 ^(23){ }^{23} 。从这些祖细胞进化到单克隆 B 淋巴细胞增多症 (MBL) 并最终演变为显性 CLL,是由额外的遗传和表观遗传异常(用闪电符号表示)、B 细胞受体 (BCR) 刺激、微环境因素和 T 细胞决定的。虚线箭头表示一种假设的机制。TD,T 细胞依赖性抗原;TI,T 细胞非依赖性抗原。图改编自 REF. 48 48 ^(48){ }^{48} , Springer Nature Limited。

200 200 ∼200\sim 200 patients with CLL have revealed the presence of 0.9 0.9 ∼0.9\sim 0.9 mutations per megabase (including point mutations, copy number alterations and exceedingly rare chromosomal translocations) and a load of 10 30 10 30 ∼10-30\sim 10-30 non-silent events per patient, with a higher number of somatic substitutions in IGHV-M CLL ( 2 , 800 2 , 800 ∼2,800\sim 2,800 ) than in IGHV-UM CLL ( 2 , 000 ) 36 45 ( 2 , 000 ) 36 45 (∼2,000)^(36-45)(\sim 2,000)^{36-45}. Overall, the mutational load in CLL is lower than in other lymphoid neoplasms and epithelial tumours, and is similar to that in acute leukaemias 46 , 47 46 , 47 ^(46,47){ }^{46,47}. In this section, we summarize the major pathways that are recurrently altered in a sizeable proportion of patients with CLL, and discuss their prognostic value as individual biomarkers (TABLE 1). We refer to other reviews that provide detailed reports of the full spectrum of genetic alterations in CLL 48 , 49 48 , 49 ^(48,49){ }^{48,49}.
200 200 ∼200\sim 200 CLL 患者揭示了每兆碱基存在 0.9 0.9 ∼0.9\sim 0.9 突变(包括点突变、拷贝数改变和极其罕见的染色体易位)和每名患者的 10 30 10 30 ∼10-30\sim 10-30 非沉默事件负荷,IGHV-M CLL ( 2 , 800 2 , 800 ∼2,800\sim 2,800 ) 中的体细胞替换数量高于 IGHV-UM CLL ( 2 , 000 ) 36 45 ( 2 , 000 ) 36 45 (∼2,000)^(36-45)(\sim 2,000)^{36-45} .总体而言,CLL 的突变负荷低于其他淋巴肿瘤和上皮肿瘤,与急性白血病相似 46 , 47 46 , 47 ^(46,47){ }^{46,47} 。在本节中,我们总结了相当一部分 CLL 患者反复改变的主要途径,并讨论了它们作为个体生物标志物的预后价值 (表 1)。我们参考了其他综述,这些综述提供了 CLL 48 , 49 48 , 49 ^(48,49){ }^{48,49} 中所有遗传改变的详细报告。
Regulation of the cell cycle and apoptosis. The most frequent genetic lesions in CLL ( 50 60 % 50 60 % ∼50-60%\sim 50-60 \% of patients) 50 50 ^(50){ }^{50} are deletions of 13q14 (del13q14) (FIG. 2; TABLE 1), which are generally monoallelic ( 80 % 80 % ∼80%\sim 80 \% of del13q14 events) and more prevalent in IGHV-M CLL than in IGHV-UM CLL 41 , 50 52 41 , 50 52 ^(41,50-52){ }^{41,50-52}. These lesions are often found to be the unique cytogenetic abnormality detectable in some CLLs, suggesting their role in the early stages of CLL development 41 , 50 , 51 41 , 50 , 51 ^(41,50,51){ }^{41,50,51}. Despite the fact that the size of 13q14 deletion is variable across patients, the minimal
细胞周期和细胞凋亡的调节。CLL( 50 60 % 50 60 % ∼50-60%\sim 50-60 \% 患者) 50 50 ^(50){ }^{50} 最常见的遗传病变是 13q14 (del13q14) 的缺失(图 2;表 1),它们通常是单等位基因(del13q14 事件 80 % 80 % ∼80%\sim 80 \% )并且在 IGHV-M CLL 中比在 IGHV-UM CLL 41 , 50 52 41 , 50 52 ^(41,50-52){ }^{41,50-52} 中更普遍。这些病变通常被发现是在某些 CLL 中可检测到的独特细胞遗传学异常,表明它们在 CLL 发展 41 , 50 , 51 41 , 50 , 51 ^(41,50,51){ }^{41,50,51} 的早期阶段的作用。尽管 13q14 缺失的大小因患者而异,但最小的

deleted region contains two long non-coding RNA genes (DLEU2 and DLEU1) and the microRNA gene cluster MIR15A-MIR16-1 (REFS 53 57 53 57 ^(53-57){ }^{53-57} ). The pathogenetic role of these deletions has been confirmed in mice with conditional deletions of the murine locus equivalent to that of the minimal deleted region in patients with CLL, which developed clonal lymphoproliferations, recapitulating the different steps of CLL initiation and progression, including monoclonal B lymphocytosis (MBL), CLL, and progression to diffuse large B cell lymphoma (DLBCL) 51 , 53 51 , 53 ^(51,53){ }^{51,53}. In vitro studies have indicated that the main mechanisms by which MIR15A-MIR16-1 exert their pathogenetic roles in B cells is through regulation of the cell cycle and apoptosis, specifically by modulating the expression of genes involved in the G 0 / G 1 S G 0 / G 1 S G_(0)//G_(1)-S\mathrm{G}_{0} / \mathrm{G}_{1}-\mathrm{S} transition (for example, inducing activation of G 1 S G 1 S G_(1)-S\mathrm{G}_{1}-\mathrm{S}-specific cyclin D2 (CCND2) and CCND3 51 51 ^(51){ }^{51} ) and the anti-apoptotic gene B C L 2 B C L 2 BCL2B C L 2 (REF. 58 58 ^(58){ }^{58} ).
缺失区包含两个长链非编码 RNA 基因 (DLEU2 和 DLEU1) 和 microRNA 基因簇 MIR15A-MIR16-1 (REFS 53 57 53 57 ^(53-57){ }^{53-57} )。这些缺失的发病作用已在小鼠基因座条件性缺失的小鼠中得到证实,与 CLL 患者的最小缺失区域相当,CLL 患者发展了克隆性淋巴增生,概括了 CLL 起始和进展的不同步骤,包括单克隆 B 淋巴细胞增多症 (MBL)、CLL 和进展为弥漫性大 B 细胞淋巴瘤 (DLBCL) 51 , 53 51 , 53 ^(51,53){ }^{51,53} .体外研究表明,MIR15A-MIR16-1 在 B 细胞中发挥致病作用的主要机制是通过调节细胞周期和细胞凋亡,特别是通过调节参与 G 0 / G 1 S G 0 / G 1 S G_(0)//G_(1)-S\mathrm{G}_{0} / \mathrm{G}_{1}-\mathrm{S} 转换的基因的表达(例如,诱导特异性细胞周期蛋白 D2 (CCND2) 和 CCND3 的激活 G 1 S G 1 S G_(1)-S\mathrm{G}_{1}-\mathrm{S} 51 51 ^(51){ }^{51} )和抗凋亡基因 B C L 2 B C L 2 BCL2B C L 2 (REF. 58 58 ^(58){ }^{58}
Since the seminal study by Döhner and colleagues 50 50 ^(50){ }^{50}, the detection of del13q14 has been associated with the best prognosis among the different copy number abnormalities (del17p, del11q and trisomy 12) (TABLE 1). Patients with CLL and del13q14 tend to have a prolonged time to first treatment (TTFT), mutations in the IGHV genes and prolonged overall survival (OS) compared with patients with other genetic abnormalities 15 , 50 15 , 50 ^(15,50){ }^{15,50}.
自 Döhner 及其同事 50 50 ^(50){ }^{50} 的开创性研究以来,del13q14 的检测与不同拷贝数异常(del17p、del11q 和 12 三体)中的最佳预后相关(表 1)。与其他遗传异常的患者相比,CLL 和 del13q14 患者的首次治疗时间 (TTFT) 往往延长,IGHV 基因突变和总生存期 (OS) 15 , 50 15 , 50 ^(15,50){ }^{15,50} 延长。