Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis

Cell Rep. 2015 Mar 3;10(8):1239-45. doi: 10.1016/j.celrep.2015.02.005. Epub 2015 Feb 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging*
  • Computational Biology
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • Hematopoiesis / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Leukemia / genetics*
  • Leukemia / pathology
  • Middle Aged
  • Mutation
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / pathology
  • Nuclear Proteins / genetics
  • Phosphoproteins / genetics
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear / genetics
  • Ribonucleoproteins / genetics
  • Sequence Analysis, DNA
  • Serine-Arginine Splicing Factors
  • Young Adult

Substances

  • Nuclear Proteins
  • Phosphoproteins
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear
  • Ribonucleoproteins
  • SF3B1 protein, human
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A