文章：

毛细胞白血病发病机制的概念演变

Evolving concepts in the pathogenesis of hairy-cell leukaemia

原文发布日期：2006-06-01

DOI: 10.1038/nrc1888

类型: Review Article

开放获取: 否

要点：

1. Hairy-cell leukaemia (HCL) is an indolent mature B-cell tumour of unknown genetic pathogenesis. Neoplastic cells have hair-like surface projections, infiltrate the bone marrow, the spleen and the liver, and circulate in low numbers in peripheral blood. Unlike other B-cell malignancies, HCL does not consistently involve the lymph nodes, does not bear chromosomal translocations and is highly sensitive to treatment with interferon-α (IFNα) and purine analogues.
2. The normal B-cell counterpart of HCL is still debated. However, its genome-wide expression signature and its mutated immunoglobulin genes suggest that HCL is derived from memory B cells, possibly from the splenic marginal zone (SMZ).
3. Clonal expansion is largely the result of increased cell survival rather than proliferation. The growth properties of HCL are regulated by intracellular signalling pathways (including mitogen activated protein kinase (MAPK) cascades) and autocrine loops (including tumour necrosis factor-α (TNFα)–TNF receptors (TNFRs)), with the microenvironment providing important pro-survival signals.
4. HCL cells home to, and remain in, blood-related compartments (bone marrow, spleen and hepatic sinusoids) through their activated integrin receptors and, probably, through the overexpression of matrix-metalloproteinase inhibitors. Conversely, chemokine receptors and adhesion proteins that are crucial for homing to the lymph nodes are downregulated.
5. Another unusual feature of HCL is bone-marrow fibrosis. Tumour cells secrete the fibrogenic cytokines basic fibroblast growth factor (bFGF) and tumour growth factor β1 (TGFβ1), which trigger the production of a fibronectin matrix by leukaemic cells and type III collagen fibres by fibroblasts, respectively.
6. 'Hairy' morphology might increase the cell surface area available for interaction with the microenvironment. Rho GTPases shape the membrane and the actin-rich cytoskeleton of HCL cells, probably with a contribution from other proteins such as pp52, growth arrest specific 7 (GAS7) and EPB4.1L2.
7. HCL-like disorders (HCL-variant (HCLv) and splenic lymphoma with villous lymphocytes (SLVL)) also present with splenomegaly, circulating 'hairy' cells and infrequent lymph node involvement, but do not respond to IFNα and purine analogues. Annexin-1 is a highly sensitive and specific HCL marker, helping in this crucial diagnostic step.
8. In the future, elucidation of the key genetic lesions and molecular factors responsible for HCL development should lead to new, specific and less immunnosuppressive drugs.

要点翻译：

1. 毛细胞白血病（HCL）是一种遗传发病机制不明的惰性成熟B细胞肿瘤。肿瘤细胞具有毛发状表面突起，可浸润骨髓、脾脏和肝脏，并在外周血中少量循环。与其他B细胞恶性肿瘤不同，HCL不持续累及淋巴结，不携带染色体易位，且对干扰素-α（IFNα）和嘌呤类似物治疗高度敏感。
2. HCL的正常B细胞对应物仍存争议。然而，其全基因组表达谱和突变的免疫球蛋白基因提示HCL可能源自记忆B细胞，尤其是脾脏边缘区（SMZ）的B细胞。
3. HCL的克隆扩增主要源于细胞存活率增加而非增殖加速。其生长特性受细胞内信号通路（包括丝裂原活化蛋白激酶（MAPK）级联反应）和自分泌环路（包括肿瘤坏死因子-α（TNFα）-TNF受体（TNFRs））调控，微环境则提供重要的促生存信号。
4. HCL细胞通过激活的整合素受体及可能存在的基质金属蛋白酶抑制剂过表达，归巢并滞留于血液相关区域（骨髓、脾脏和肝血窦）。相反，对淋巴结归巢至关重要的趋化因子受体和黏附蛋白表达下调。
5. HCL的另一异常特征是骨髓纤维化。肿瘤细胞分泌成纤维细胞因子碱性成纤维细胞生长因子（bFGF）和肿瘤生长因子β1（TGFβ1），分别触发白血病细胞产生纤连蛋白基质和成纤维细胞产生III型胶原纤维。
6. "毛发状"形态可能增加细胞与微环境相互作用的表面积。Rho GTP酶与pp52、生长阻滞特异性蛋白7（GAS7）及EPB4.1L2等蛋白共同调控HCL细胞的膜形态和富含肌动蛋白的细胞骨架。
7. HCL样疾病（HCL变异型（HCLv）和绒毛淋巴细胞脾淋巴瘤（SLVL））同样表现为脾肿大、循环"毛细胞"及罕见淋巴结累及，但对IFNα和嘌呤类似物无反应。膜联蛋白-1作为HCL的高敏感性和特异性标志物，在这一关键诊断步骤中具有重要价值。
8. 未来，阐明HCL发病的关键遗传损伤和分子因子将有望推动新型、特异性且免疫抑制性更低药物的研发。

英文摘要：

Hairy-cell leukaemia (HCL) has long been recognized as distinct from other chronic B-cell malignancies, but several questions remain unanswered. What is the HCL cell of origin? Why does HCL lack the hallmarks of most mature B-cell tumours (for example, chromosomal translocations and consistent lymph node involvement) and show unique features like 'hairy' morphology and bone-marrow fibrosis? Gene-expression profiling and other studies have recently provided new insights into HCL biology and have the potential to affect clinical practice.

摘要翻译： 

毛细胞白血病（HCL）长期以来被认为与其他慢性B细胞恶性肿瘤不同，但仍有一些问题尚未解答。HCL的细胞起源是什么？为什么HCL缺乏大多数成熟B细胞肿瘤的特征（例如染色体易位和持续的淋巴结受累），却表现出“毛状”形态和骨髓纤维化等独特特征？基因表达谱分析和其他研究最近为HCL的生物学提供了新的见解，并有潜力影响临床实践。

原文链接：

Evolving concepts in the pathogenesis of hairy-cell leukaemia