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Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential
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Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential
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Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential
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Journal Article
Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential
2018
Overview
Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including
TP53
and
PPM1D
. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However,
DNMT3A
mutant clones often expand, while
PPM1D
mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-
TP53
DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.
Cellular stressors can impact clonal hematopoiesis. Here, the authors explore the impact of cytotoxic therapy and hematopoietic transplantation on clonal expansion, suggesting different stressors can promote expansion of distinct long-lived clones.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 45/100
/ 45/22
/ 45/23
/ 45/77
/ Adult
/ Aged
/ Antineoplastic Agents - pharmacology
/ Clone Cells - radiation effects
/ DNA
/ DNA (Cytosine-5-)-Methyltransferases - genetics
/ Female
/ Genes
/ Hematopoietic Stem Cell Transplantation
/ Hematopoietic Stem Cells - drug effects
/ Hematopoietic Stem Cells - radiation effects
/ Humanities and Social Sciences
/ Humans
/ Leukemia
/ Male
/ Mutation
/ Protein Phosphatase 2C - genetics
/ Science
/ Therapy
