Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential
Year: 2018
Type: article
Study design: Observational Study
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.
Source: Nature Communications
Authors: 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, Daniel C. Link
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1114310655, G12431752, G1674664843, G1689576311, G2804094967, G299873027, Clonal Evolution of Hematopoietic Stem Cells During Chemotherapy and Transplantation, G8242737674, Genomics Of Acute Myeloid Leukemia., G9000012855, G9000155930, G9000319192, G9000355869, Molecular Pathogenesis of Acute Myeloid Leukemia, Comprehensive Informatic Analyses of AML Genomes and Epigenomes, Washington University Institute of Clinical and Translational Sciences, Specialized Program of Research Excellence (SPORE) in Leukemia, Cancer Center Support Grant
OpenAlex ID: W2790610652