Benítez Leticia, Fischer Ute, Crispi Fàtima, Castro-Barquero Sara, Crovetto Francesca, Larroya Marta, Youssef Lina, Kameri Ersen, Castillo Helena, Bueno Clara, Casas Rosa, Borras Roger, Vieta Eduard, Estruch Ramon, Menéndez Pablo, Borkhardt Arndt, Gratacós Eduard
BCNatal|Fetal Medicine Research Center, Hospital Clínic and Hospital Sant Joan de Deu, University of Barcelona, 08950 Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
Int J Mol Sci. 2025 Mar 25;26(7):2971. doi: 10.3390/ijms26072971.
-positive pediatric acute lymphoblastic leukemia frequently has a prenatal origin and follows a two-hit model: a first somatic alteration leads to the formation of the oncogenic fusion gene and the generation of a preleukemic clone in utero. Secondary hits after birth are necessary to convert the preleukemic clone into clinically overt leukemia. However, prenatal factors triggering the first hit have not yet been determined. Here, we explore the influence of maternal factors during pregnancy on the prevalence of the fusion. To this end, we employed a nested interventional cohort study (IMPACT-BCN trial), including 1221 pregnancies (randomized into usual care, a Mediterranean diet, or mindfulness-based stress reduction) and determined the prevalence of the fusion gene in the DNA of cord blood samples at delivery ( = 741) using the state-of-the-art GIPFEL (genomic inverse PCR for exploration of ligated breakpoints) technique. A total of 6.5% ( = 48 of 741) of healthy newborns tested positive for . Our multiple regression analyses showed a trend toward lower prevalence in offspring of the high-adherence intervention groups. Strikingly, corticosteroid use for lung maturation during pregnancy was significantly associated with (adjusted OR 3.9, 95% CI 1.6-9.8) in 39 neonates, particularly if applied before 26 weeks of gestation (OR 7.7, 95% CI 1.08-50) or if betamethasone (OR 4.0, 95% CI 1.4-11.3) was used. Prenatal exposure to corticosteroids within a critical time window may therefore increase the risk of developing + preleukemic clones and potentially leukemia after birth. Taken together, this study indicates that preleukemia prevalence may be modulated and potentially prevented.
阳性小儿急性淋巴细胞白血病通常起源于产前，并遵循二次打击模型：第一次体细胞改变导致致癌融合基因的形成，并在子宫内产生白血病前期克隆。出生后的二次打击对于将白血病前期克隆转化为临床明显的白血病是必要的。然而，触发第一次打击的产前因素尚未确定。在这里，我们探讨孕期母亲因素对融合基因流行率的影响。为此，我们采用了一项嵌套式干预队列研究（IMPACT-BCN试验），纳入1221例妊娠（随机分为常规护理、地中海饮食或基于正念的减压组），并使用最先进的GIPFEL（用于探索连接断点的基因组反向PCR）技术，在分娩时测定脐带血样本DNA中融合基因的流行率（n = 741）。共有6.5%（741例中的48例）健康新生儿检测出融合基因阳性。我们的多元回归分析显示，高依从性干预组后代的融合基因流行率有降低趋势。令人惊讶的是，孕期使用皮质类固醇促进肺成熟与39例新生儿的融合基因显著相关（校正比值比3.9，95%可信区间1.6 - 9.8），特别是在妊娠26周前使用（比值比7.7，95%可信区间1.08 - 50）或使用倍他米松（比值比4.0，95%可信区间1.4 - 11.3）时。因此，在关键时间窗口内产前暴露于皮质类固醇可能会增加出生后发生融合基因阳性白血病前期克隆以及潜在白血病的风险。综上所述，这项研究表明融合基因阳性白血病前期的流行率可能受到调节并有可能预防。
