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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\u2010B\u2010cell acute lymphoblastic leukemia, are age\u2010restricted. 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\u2010infant pre\u2010B\u2010cell 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.<\/jats:p>","DOI":"10.1111\/imr.13180","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T08:04:36Z","timestamp":1672646676000},"page":"197-215","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Layered immunity and layered leukemogenicity: Developmentally restricted mechanisms of pediatric leukemia initiation"],"prefix":"10.1111","volume":"315","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9558-152X","authenticated-orcid":false,"given":"Jonny","family":"Mendoza\u2010Castrejon","sequence":"first","affiliation":[{"name":"Department of Pediatrics Division of Hematology and Oncology  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0766-4200","authenticated-orcid":false,"given":"Jeffrey A.","family":"Magee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Hematology and Oncology  St. Louis Missouri USA"},{"name":"Department of Genetics Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,2]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"SEER Pediatric Monograph","author":"Smith M","year":"1999"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00211-8"},{"issue":"10","key":"e_1_2_10_4_1","first-page":"3534","article-title":"Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. 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