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

Terrence N. Wong, Christopher A. Miller, Matthew R. M. Jotte, Nusayba Bagegni, Jack D. Baty, Amy P. Schmidt, Amanda F. Cashen, Eric J. Duncavage, Nichole M. Helton, Mark Fiala, Robert S. Fulton, Sharon E. Heath, Megan Janke, Kierstin Luber, Peter Westervelt, Ravi Vij, John F. DiPersio, John S. Welch, Timothy A. Graubert, Matthew J. Walter, Timothy J. Ley and Daniel C. Link ()
Additional contact information
Terrence N. Wong: Washington University School of Medicine
Christopher A. Miller: Washington University School of Medicine
Matthew R. M. Jotte: Washington University School of Medicine
Nusayba Bagegni: Washington University School of Medicine
Jack D. Baty: Washington University
Amy P. Schmidt: Washington University School of Medicine
Amanda F. Cashen: Washington University School of Medicine
Eric J. Duncavage: Washington University School of Medicine
Nichole M. Helton: Washington University School of Medicine
Mark Fiala: Washington University School of Medicine
Robert S. Fulton: Washington University School of Medicine
Sharon E. Heath: Washington University School of Medicine
Megan Janke: Washington University School of Medicine
Kierstin Luber: Washington University School of Medicine
Peter Westervelt: Washington University School of Medicine
Ravi Vij: Washington University School of Medicine
John F. DiPersio: Washington University School of Medicine
John S. Welch: Washington University School of Medicine
Timothy A. Graubert: Massachusetts General Hospital
Matthew J. Walter: Washington University School of Medicine
Timothy J. Ley: Washington University School of Medicine
Daniel C. Link: Washington University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-02858-0

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