Layered immunity and layered leukemogenicity: Developmentally restricted mechanisms of pediatric leukemia initiation

Immunol Rev. 2023 May;315(1):197-215. doi: 10.1111/imr.13180. Epub 2023 Jan 2.


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.

Keywords: age-biased mutation profiles; age-restricted leukemias; layered immunity; pediatric leukemia.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Child
  • Child, Preschool
  • Hematopoietic Stem Cells
  • Humans
  • Infant, Newborn
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / pathology
  • Mutation / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma*