Somatic Mutations Reveal Lineage Relationships and Age-Related Mutagenesis in Human Hematopoiesis
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Osorio, Fernando G.; Huber, Axel Rosendahl; Oka, Rurika; Verheul, Mark; Patel, Sachin H.; Hasaart, Karlijn; Fonteijne, Lisanne de la; Varela Egocheaga, Ignacio
Fecha
2018Derechos
Attribution-NonCommercial-NoDerivatives 4.0 International
Publicado en
Cell Rep. 2018 Nov 27;25(9):2308-2316.e4
Editorial
Elsevier
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Palabras clave
HSC
Developmental Lineage Tree
Human Hematopoiesis
Leukemia
Mutational Processes
Somatic Mutations
Resumen/Abstract
Mutation accumulation during life can contribute to
hematopoietic dysfunction; however, the underlying
dynamics are unknown. Somatic mutations in blood
progenitors can provide insight into the rate and processes
underlying this accumulation, as well as the
developmental lineage tree and stem cell division
numbers. Here,we catalog mutations in the genomes
of human-bone-marrow-derived and umbilical-cordblood-
derived hematopoietic stem and progenitor
cells (HSPCs). We find that mutations accumulate
gradually during life with approximately 14 base substitutions
per year. The majority of mutations were
acquired after birth and could be explained by the
constant activity of various endogenous mutagenic
processes, which also explains the mutation load in
acute myeloid leukemia (AML). Using these mutations,
we construct a developmental lineage tree of
human hematopoiesis, revealing a polyclonal architecture
and providing evidence that developmental
clones exhibit multipotency. Our approach highlights
features of human native hematopoiesis and its
implications for leukemogenesis.
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