Greaves M
LRF Centre for the Cell and Molecular Biology of Leukaemia, Institute of Cancer Research, Chester Beatty Laboratories, London, U.K.
Eur J Cancer. 1999 Dec;35(14):1941-53. doi: 10.1016/s0959-8049(99)00296-8.
The patterns of genetic change, clonal evolution, natural history and latency are very different in the paediatric leukaemias compared with adult epithelial cancers but are similar to those in other childhood cancers of mesenchymal stem cell origin. This distinction has a biological logic in the context of the selective pressures for clonal emergence in different developmental and cellular contexts and has a major impact on curability. Most childhood leukaemias and some other mesenchymal stem cell tumours are of fetal origin and can metastasize without corruption of restraints on cell proliferation or bypassing apoptosis. In marked contrast to most invasive or metastatic epithelial carcinomas in adults, these former cancers then retain sensitivity to therapeutic apoptosis. Moreover, their abbreviated and less complex evolutionary status is associated with less genetic diversity and instability, minimising opportunity for clonal selection for resistance. A minority of leukaemias in children and a higher fraction in adults do, however, have genetic alterations that bypass cell cycle controls and apoptosis imposition. These are the 'bad news' genotypes. The cellular and molecular diversity of acute leukaemia impacts also on aetiology. Paediatric acute leukaemias can be initiated prenatally by illegitimate recombination and fusion gene formation in fetal haemopoiesis. For acute lymphoblastic leukaemia (ALL) in children, twin studies suggest that a secondary postnatal molecular event is also required. This may be promoted by an abnormal or delayed response to common infections. Even for a classic case of a cancer that is intrinsically curable by systematic chemotherapy i.e. childhood ALL, prevention may turn out to be the preferred option.
与成人上皮癌相比，儿童白血病的基因变化模式、克隆进化、自然史和潜伏期有很大不同，但与其他源自间充质干细胞的儿童癌症相似。在不同发育和细胞背景下克隆出现的选择压力背景下，这种差异具有生物学逻辑，并且对治愈率有重大影响。大多数儿童白血病和一些其他间充质干细胞肿瘤起源于胎儿，并且可以在不破坏细胞增殖限制或绕过细胞凋亡的情况下发生转移。与大多数成人侵袭性或转移性上皮癌形成鲜明对比的是，这些癌症随后对治疗性细胞凋亡仍保持敏感性。此外，它们简短且不太复杂的进化状态与较少的基因多样性和不稳定性相关，从而将克隆选择产生耐药性的机会降至最低。然而，少数儿童白血病和较高比例的成人白血病确实存在绕过细胞周期控制和细胞凋亡的基因改变。这些就是“坏消息”基因型。急性白血病的细胞和分子多样性也对病因学有影响。儿童急性白血病可在产前由胎儿造血过程中的非法重组和融合基因形成引发。对于儿童急性淋巴细胞白血病（ALL），双胞胎研究表明还需要一个出生后的二次分子事件。这可能由对常见感染的异常或延迟反应所促进。即使对于一种本质上可通过系统化疗治愈的典型癌症病例，即儿童ALL，预防可能最终会成为首选方案。
