Layered immunity and layered leukemogenicity: Developmentally restricted mechanisms of pediatric leukemia initiation
Year: 2023
Type: review
Abstract: 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.
Source: Immunological Reviews
DOI: 10.1111/imr.13180
Authors: Jonny Mendoza‐Castrejon, Jeffrey A. Magee
Institution: Washington University in St. Louis
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Alex's Lemonade Stand Foundation for Childhood Cancer, Leukemia and Lymphoma Society, Edward P. Evans Foundation, Children's Discovery Institute, National Institutes of Health, Research Committee, Aristotle University of Thessaloniki, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences
Awards: The influence of proteostasis loss in aging hematopoietic stem cells on leukemia initiation, University of Michigan Postbaccalaureate Research Education Program (UM PREP), TEMPORAL CHANGES IN MECHANISMS OF HSC SELF-RENEWAL AND MYELOID LEUKEMOGENESIS, G7177815877, G7345521691, G8016387634, Molecular Oncology Training Grant, The role of Kmt2c/MLL3 in hematopoietic stem cell self-renewal, commitment and exhaustion
OpenAlex ID: W4313423907