文章：

BCR-ABL在慢性髓性白血病发病机制中的作用

Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia

原文发布日期：2005-02-18

DOI: 10.1038/nrc1567

类型: Review Article

开放获取: 否

要点：

1. Chronic myelogenous leukaemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. Clinical and laboratory studies indicate that the fusion protein BCR–ABL is essential for initiation, maintenance and progression of CML, yet the transformation of CML from chronic phase to blast phase requires additional genetic and/or epigenetic abnormalities.
2. Imatinib — an inhibitor of the tyrosine-kinase activity of BCR–ABL — has been successfully used to treat patients with chronic-phase CML, but residual disease persists and drug resistance emerges. It is therefore important to identify other factors involved in the pathogenesis of CML, to design alternative treatment strategies.
3. Transgenic expression of BCR–ABL in mice leads to a myeloproliferative disorder that resembles the chronic phase of CML in patients. The ABL tyrosine-kinase activity is necessary but not sufficient to induce CML-like disease in mice. So, additional activities of BCR–ABL, beyond its kinase activity, are important for leukaemogenesis.
4. BCR–ABL also interacts with oncogenic transcription factors to induce a form of acute myelogenous leukaemia that resembles the blast phase of CML, indicating that disease progression involves cooperation between BCR–ABL and mutations that disrupt haematopoietic gene transcription.
5. CML progenitor cells seem to be refractory to imatinib therapy, indicating that the biology of haematopoietic stem/progenitor cells and tumour microenvironment are likely to contribute to the disease development and maintenance.

要点翻译：

1. 慢性髓系白血病（CML）源于造血干细胞的肿瘤性转化。临床和实验室研究表明，BCR-ABL融合蛋白对CML的起始、维持和进展至关重要，但CML从慢性期向急变期转化需要额外的遗传和/或表观遗传异常。
2. 伊马替尼——一种BCR-ABL酪氨酸激酶活性抑制剂——已成功用于慢性期CML患者的治疗，但残留病变持续存在且会出现耐药性。因此，识别参与CML发病机制的其他因素对设计替代治疗策略具有重要意义。
3. BCR-ABL转基因表达可导致小鼠出现类似人类慢性期CML的骨髓增殖性疾病。ABL酪氨酸激酶活性是诱导小鼠CML样疾病的必要条件但非充分条件。因此，BCR-ABL除激酶活性外的其他功能对白血病发生至关重要。
4. BCR-ABL还可与致癌转录因子相互作用，诱导产生类似CML急变期的急性髓系白血病，这表明疾病进展涉及BCR-ABL与破坏造血基因转录的突变之间的协同作用。
5. CML祖细胞似乎对伊马替尼治疗不敏感，这表明造血干细胞/祖细胞生物学特性及肿瘤微环境可能共同促进疾病的发生与维持。

英文摘要：

Imatinib, a potent inhibitor of the oncogenic tyrosine kinase BCR–ABL, has shown remarkable clinical activity in patients with chronic myelogenous leukaemia (CML). However, this drug does not completely eradicate BCR–ABL-expressing cells from the body, and resistance to imatinib emerges. Although BCR–ABL remains an attractive therapeutic target, it is important to identify other components involved in CML pathogenesis to overcome this resistance. What have clinical trials of imatinib and studies using mouse models for BCR–ABL leukaemogenesis taught us about the functions of BCR–ABL beyond its kinase activity, and how these functions contribute to CML pathogenesis?

摘要翻译： 

伊马替尼是一种可有效抑制致癌性酪氨酸激酶BCR–ABL的药物，在慢性髓性白血病（CML）患者中表现出显著的临床疗效。然而，该药物并不能从体内彻底清除表达BCR–ABL的细胞，且会出现耐药。尽管BCR–ABL仍是极具吸引力的治疗靶点，但为克服耐药，有必要找出参与CML发病的其他组分。伊马替尼的临床试验以及利用小鼠模型研究BCR–ABL致白血病的实验，让我们了解到BCR–ABL除激酶活性外的哪些功能，这些功能又是如何参与CML发病的？

原文链接：

Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia