Pediatric Hematology-Oncology Research Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Pediatric Hematology-Oncology Research Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Arch Med Res. 2016 Nov;47(8):593-606. doi: 10.1016/j.arcmed.2016.11.014.
The understanding of leukemogenesis in early-age acute leukemia (EAL) has improved remarkably. Initiating somatic mutations detected in dried neonatal blood spots (DNBS) and in cord blood samples of affected children with leukemia have been proven to be acquired prenatally. However, to date, few epidemiological studies have been carried out exploring EAL that include infants and children 13-24 months of age at the diagnosis. Maternal exposure to transplacental DNA-damaging substances during pregnancy has been suggested to be a risk factor for EAL. Most cases of infants with acute lymphoblastic (i-ALL) or myeloid leukemia (i-AML) have KMT2A gene rearrangements (KMT2A-r), which disturb its essential role as an epigenetic regulator of hematopoiesis. Due to the short latency period for EAL and the fact that KMT2A-r resembles those found in secondary AML, exposure to topoisomerase II inhibitors has been associated with transplacental risk as proxi for causality. EAL studies have been conducted in Brazil for over two decades, combining observational epidemiology, leukemia biology, and clinical data. EAL was investigated considering (i) age strata (infants vs. 13-24 months-old); (ii) somatic mutations associated with i-ALL and i-AML; (iii) ethnic-geographic variations; (iv) contribution of maternal genotypes; and (v) time latency of exposures and mutations in DNBS. Interactions of acquired and constitutive gene mutations are challenging tools to test risk factor associations for EAL. In this review we summarize the EAL scenario (including B-cell precursor-ALL, T-ALL, and AML) results combining environmental and genetic susceptibility risk factors and we raise questions that should be considered for further action.
早发性急性白血病（EAL）发病机制的研究已取得显著进展。在患有白血病的新生儿干血斑（DNBS）和脐带血样本中检测到的起始体细胞突变已被证实是产前获得的。然而，迄今为止，很少有流行病学研究探讨包括 13-24 个月大的婴儿和儿童在内的 EAL。有研究提示，母亲在怀孕期间接触胎盘内的 DNA 损伤物质是 EAL 的危险因素。大多数患有急性淋巴细胞白血病（i-ALL）或急性髓细胞白血病（i-AML）的婴儿病例都存在 KMT2A 基因重排（KMT2A-r），这会干扰其作为造血细胞表观遗传调节剂的基本功能。由于 EAL 的潜伏期较短，且 KMT2A-r 类似于继发性 AML 中发现的基因重排，因此，拓扑异构酶 II 抑制剂的暴露与胎盘内的风险因素有关，提示可能存在因果关系。二十多年来，巴西一直在进行 EAL 研究，将观察性流行病学、白血病生物学和临床数据相结合。EAL 的研究考虑了以下几个方面：（i）年龄分层（婴儿与 13-24 个月龄）；（ii）与 i-ALL 和 i-AML 相关的体细胞突变；（iii）种族地理差异；（iv）母体基因型的贡献；以及（v）DNBS 中暴露和突变的潜伏期。获得性和组成性基因突变的相互作用是检验 EAL 危险因素相关性的具有挑战性的工具。在这篇综述中，我们总结了 EAL 的发病情况（包括 B 细胞前体-ALL、T-ALL 和 AML）结果，综合了环境和遗传易感性危险因素，并提出了一些需要进一步研究的问题。
