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

Jonny Mendoza-Castrejon1, Jeffrey A Magee1,2

  • 1Department of Pediatrics, Division of Hematology and Oncology, St. Louis, Missouri, USA.

Immunological Reviews
|January 2, 2023
PubMed

Insights

Pediatric leukemias are linked to developmental changes in hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs). Understanding these age-related transformations offers new therapeutic targets for childhood cancers.

Area of Science:

  • Hematology
  • Developmental Biology
  • Oncology

Background:

  • Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) change significantly throughout life.
  • These ontogenetic shifts influence pediatric leukemia initiation mechanisms.
  • Immune cell development is layered, with some cells originating exclusively from fetal HSCs/MPPs.

Purpose of the Study:

  • To explore the link between ontogenetic changes in HSCs/MPPs and age-restricted pediatric leukemias.
  • To investigate how transcriptional and epigenetic reprogramming affects immune output and leukemogenicity.
  • To identify potential therapeutic targets by examining interactions between leukemogenic mutations and developmental pathways.

Main Methods:

  • Comparative analysis of HSC/MPP properties across different life stages (fetal, neonatal, juvenile, adult).
  • Examination of transcriptional and epigenetic reprogramming in HSCs/MPPs.
  • Analysis of mutation profiles in various pediatric leukemias and comparison with adult leukemias.

Main Results:

  • Some pediatric leukemias are age-restricted, suggesting they arise from fetal progenitors that lose transformation competence with age.
  • Childhood leukemias exhibit distinct mutation profiles compared to adult leukemias, indicating age-dependent mutagenesis or progenitor response.
  • Layered immunity derived from distinct HSC/MPP waves may underlie a parallel layered leukemogenicity.

Conclusions:

  • Age-specific changes in hematopoietic stem cells and progenitor cells are critical in pediatric leukemia development.
  • Understanding these developmental dynamics and their interaction with mutations is key to targeting childhood leukemias.
  • Therapeutic strategies could exploit normal developmental switches to treat leukemias arising from specific progenitor populations.

Keywords:
age-biased mutation profilesage-restricted leukemiaslayered immunitypediatric leukemia

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