McHale Cliona M, Smith Martyn T
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California 94720-7360, USA.
Am J Hematol. 2004 Apr;75(4):254-7. doi: 10.1002/ajh.20030.
We, and others, have demonstrated an in utero origin for translocations associated with childhood leukemia, with latency periods in some cases exceeding 10 years. The mechanism of generation of most of the translocations is thought to be aberrant repair following abortive apoptosis, rather than V(D)J recombination or exposure to topoisomerase II inhibitors. Folate supplementation may prevent some of the chromosome breakage leading to translocation formation. Translocations t(8;21) and t(12;21) have been shown to occur in the normal population (before birth) at a frequency that is 100-fold greater than the risk of developing the corresponding leukemia. In most instances, additional genetic changes are required for progression to leukemia. Tyrosine kinase receptor (RTK) mutations, which give cells a survival/proliferative advantage, are proposed to act cooperatively with fusion genes, leading to transformation. However, translocations and cooperating RTK mutations have not been identified for all leukemia subtypes, particularly in acute myeloid leukemia. The core binding transcriptional pathway is frequently targeted by translocation in utero. We propose that this pathway is highly sensitive during fetal hematopoiesis and may be targeted by mechanisms other than translocation. For each leukemia subtype it is important to characterize the corresponding leukemic stem cell, which is thought to be the initial target for translocation. This would help to elucidate the molecular pathways involved in the progression from preleukemic clone harboring a translocation to fully disseminated leukemia.
我们以及其他研究人员已经证明，与儿童白血病相关的易位起源于子宫内，在某些情况下潜伏期超过10年。大多数易位的产生机制被认为是流产性凋亡后的异常修复，而非V(D)J重组或接触拓扑异构酶II抑制剂。补充叶酸可能会预防一些导致易位形成的染色体断裂。已表明易位t(8;21)和t(12;21)在正常人群（出生前）中的发生频率比患相应白血病的风险高100倍。在大多数情况下，白血病进展还需要其他基因变化。酪氨酸激酶受体（RTK）突变赋予细胞生存/增殖优势，被认为与融合基因协同作用，导致细胞转化。然而，并非所有白血病亚型都已鉴定出易位和协同的RTK突变，尤其是在急性髓系白血病中。核心结合转录途径在子宫内常因易位而成为靶点。我们认为该途径在胎儿造血过程中高度敏感，可能会受到易位以外的机制影响。对于每种白血病亚型，表征相应的白血病干细胞很重要，白血病干细胞被认为是易位的初始靶点。这将有助于阐明从携带易位的白血病前期克隆发展到完全播散性白血病所涉及的分子途径。
