造血干细胞（HSC）和多能祖细胞（MPP）在胚胎发育过程中相继产生，它们的特性在一生中发生了显著变化。HSC/MPP的本体学变化体现了儿童白血病起始机制的相应变化。随着HSC和MPP从胎儿、新生儿、幼儿和成年阶段的发展，它们经历了转录和表观遗传重编程，修改免疫功能来应对特定年龄的致病挑战。有些免疫细胞只来自胎儿HSC/MPP。我们认为这种层次免疫指导下的细胞命运是导致平行层次白血病发生的基础。事实上，一些儿童白血病，如儿童髓系单核细胞白血病、唐氏综合征髓系白血病和婴儿前B细胞急性淋巴细胞白血病，是年龄限制性的，只在婴幼儿时期出现。这些白血病可能起源于随着年龄增长而失去转化能力的胎儿祖细胞。其他儿童白血病，如非婴儿前B细胞急性淋巴细胞白血病和急性髓系白血病，具有儿童常见而在形态相似的成人白血病中罕见的突变谱。这些差异可能反映了突变发生机制的时间变化或祖细胞在不同年龄对给定突变的响应方式的变化。白血病发生突变和正常发育开关之间的相互作用为疗法提供了潜在的靶点。 © 2023 John Wiley＆Sons A / S。由John Wiley＆Sons Ltd.出版。

Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) arise in successive waves during ontogeny, and their properties change significantly throughout life. Ontological changes in HSCs/MPPs underlie corresponding changes in mechanisms of pediatric leukemia initiation. As HSCs and MPPs progress from fetal to neonatal, juvenile and adult stages of life, they undergo transcriptional and epigenetic reprogramming that modifies immune output to meet age-specific pathogenic challenges. Some immune cells arise exclusively from fetal HSCs/MPPs. We propose that this layered immunity instructs cell fates that underlie a parallel layered leukemogenicity. Indeed, some pediatric leukemias, such as juvenile myelomonocytic leukemia, myeloid leukemia of Down syndrome, and infant pre-B-cell acute lymphoblastic leukemia, are age-restricted. They only present during infancy or early childhood. These leukemias likely arise from fetal progenitors that lose competence for transformation as they age. Other childhood leukemias, such as non-infant pre-B-cell acute lymphoblastic leukemia and acute myeloid leukemia, have mutation profiles that are common in childhood but rare in morphologically similar adult leukemias. These differences could reflect temporal changes in mechanisms of mutagenesis or changes in how progenitors respond to a given mutation at different ages. Interactions between leukemogenic mutations and normal developmental switches offer potential targets for therapy.© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.