Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential

Terrence N. Wong, Christopher Miller, Matthew R.M. Jotte, Nusayba Bagegni, Jack D. Baty, Amy P. Schmidt, Amanda Cashen, Eric Duncavage, Nichole M. Helton, Mark Fiala, Robert Fulton, Sharon E. Heath, Megan Janke, Kierstin Luber, Peter Westervelt, Ravi Vij, John Dipersio, John Welch, Timothy A. Graubert, Matthew WalterTimothy Ley, Daniel Link

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

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.

Original languageEnglish
Article number455
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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