Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain.
Leukemia. 2011 Mar;25(3):400-10. doi: 10.1038/leu.2010.284. Epub 2010 Dec 7.
Infant acute lymphoblastic leukemia (ALL) involving mixed-lineage leukemia (MLL) fusions has attracted a huge interest in basic and clinical research because of its prenatal origin, mixed-lineage phenotype, dismal prognosis and extremely short latency. Over 90% of infant ALLs are pro-B ALL harboring the leukemic fusion MLL-AF4. Despite the fact that major achievements have provided a better understanding about the etiology of infant MLL-AF4+ ALL over the last two decades, key questions remain unanswered. Epidemiological and genetic studies suggest that the in utero origin of MLL rearrangements in infant leukemia may be the result of prenatal exposure to genotoxic compounds. In fact, chronic exposure of human embryonic stem cells (hESCs) to etoposide induces MLL rearrangements and makes hESC more prone to acquire subsequent chromosomal abnormalities than postnatal CD34(+) cells, linking embryonic exposure to topoisomerase II inhibitors to genomic instability and MLL rearrangements. Unfortunately, very little is known about the nature of the target cell for transformation. Neuron-glial antigen 2 expression was initially claimed to be specifically associated with MLL rearrangements and was recently shown to be readily expressed in CD34+CD38+, but not CD34+CD38- cells suggesting that progenitors rather than stem cells may be the target cell for transformation. Importantly, the recent findings showing that MLL-AF4 rearrangement is present and expressed in mesenchymal stem cells from infant patients with MLLAF4+ ALL challenged our current view of the etiology and cellular origin of this leukemia. It becomes therefore crucial to determine where the leukemia relapses come from and how the tumor-stroma relationship is defined at the molecular level. Finally, MLL-AF4 leukemogenesis has been particularly difficult to model and bona fide MLL-AF4 disease models do not exist so far. It is likely that the current disease models are missing some essential ingredients of leukemogenesis in the human embryo/fetus. We thus propose modeling MLL-AF4+ infant pro-B ALL using prenatal hESCs.
婴儿急性淋巴细胞白血病（ALL）伴混合谱系白血病（MLL）融合，由于其先天起源、混合谱系表型、预后不良和潜伏期极短，在基础和临床研究中引起了极大的兴趣。超过 90%的婴儿 ALL 是具有白血病融合 MLL-AF4 的前 B 细胞 ALL。尽管过去二十年的重大研究成果使我们对婴儿 MLL-AF4+ALL 的病因有了更好的了解，但仍有一些关键问题尚未得到解答。流行病学和遗传学研究表明，婴儿白血病中 MLL 重排的先天起源可能是产前暴露于遗传毒性化合物的结果。事实上，依托泊苷慢性暴露于人类胚胎干细胞（hESC）中会诱导 MLL 重排，并使 hESC 比产后 CD34(+)细胞更容易获得随后的染色体异常，将胚胎暴露于拓扑异构酶 II 抑制剂与基因组不稳定性和 MLL 重排联系起来。不幸的是，对于转化的靶细胞性质，我们知之甚少。神经胶质抗原 2 的表达最初被认为与 MLL 重排特异性相关，最近的研究表明，它很容易在 CD34+CD38+细胞中表达，但在 CD34+CD38-细胞中不表达，这表明祖细胞而不是干细胞可能是转化的靶细胞。重要的是，最近的研究发现，MLL-AF4 重排在婴儿 MLL-AF4+ALL 患者的间充质干细胞中存在并表达，这对我们目前对这种白血病的病因和细胞起源的看法提出了挑战。因此，确定白血病复发的来源以及肿瘤-基质关系在分子水平上的定义变得至关重要。最后，MLL-AF4 白血病的发生特别难以建模，到目前为止还没有真正的 MLL-AF4 疾病模型。目前的疾病模型可能缺少人类胚胎/胎儿中白血病发生的一些必要成分。因此，我们建议使用产前 hESC 来模拟 MLL-AF4+婴儿前 B 细胞 ALL。
