in the bone marrow
The incidence of clonal hematopoiesis in the general population may be higher than we thought and appears to increase dramatically with age, according to research published in Cell Reports.
Investigators used ultra-deep sequencing to search for evidence of clonal hematopoiesis driven by 15 recurrent leukemogenic mutations.
They sequenced DNA from more than 4000 subjects who had no evidence of hematologic malignancy.
And the incidence of clonal hematopoiesis was higher than has been observed in previous, exome-sequencing studies—0.8% in subjects under 60, rising to 19.5% in subjects ages 90 to 98.
“Ultra-deep sequencing has allowed us to see the very beginnings of cancer,” said study author George Vassiliou, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“These mutations will be harmless for the majority of people, but, for a few unlucky carriers, they will take the body on a journey towards leukemia. We are now beginning to understand the major landmarks on that journey.”
The investigators found that mutations affecting 2 genes, SF3B1 and SRSF2, appeared exclusively in 70-year-olds.
This suggests these mutations only confer a growth benefit for cells later in life, when there is less competition. And it explains why myelodysplastic syndromes, which are associated with these genes, appear almost exclusively in the elderly.
None of the 4219 subjects studied had mutations in the NPM1 gene, which is mutated in up to 40% of leukemia cases.
This unexpected result suggests that mutations in NPM1 behave as gatekeepers for leukemia, the investigators said. Once a mutation in this gene occurs in a cell with particular, previously accumulated, pre-leukemic mutations, leukemia will develop.
“The significance of mutations in this gene is astonishingly clear from these results: it simply doesn’t exist where there is no leukemia,” said study author Naomi Park, PhD, of the Wellcome Trust Sanger Institute.
“When it is mutated in the appropriate cell, the floodgates open, and leukemia is then very likely to develop. This fits with studies we’ve conducted in the past in which we found that the gene primes blood stem cells for leukemic transformation.”
