Leukemia-Associated Somatic Mutations Drive Distinct Patterns of Age-Related Clonal Hemopoiesis

Thomas McKerrell, Naomi Park, Thaidy Moreno, Carolyn S. Grove, Hannes Ponstingl, Jonathan Stephens, Charles Crawley, Jenny Craig, Mike A. Scott, Clare Hodkinson, Joanna Baxter, Roland Rad, Duncan R. Forsyth, Michael A. Quail, Eleftheria Zeggini, Willem Ouwehand, Ignacio Varela, George S. Vassiliou, Society Scientific Group Understanding Society Scientific Group

Research output: Contribution to journalArticlepeer-review

401 Scopus citations

Abstract

Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged 70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age.

Original languageEnglish
Pages (from-to)1239-1245
Number of pages7
JournalCell Reports
Volume10
Issue number8
DOIs
StatePublished - 3 Mar 2015
Externally publishedYes

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