Massive expansion of multiple clones in the mouse hematopoietic system long after whole-body X-irradiation

Abstract

Clonal hematopoiesis (CH) is prevalent in the elderly and associates with hematologic malignancy and cardiovascular disease. Although the risk of developing these diseases increases with radiation doses in atomic-bomb survivors, the causal relationship between radiation exposure and CH is unclear. This study investigated whether radiation exposure induces CH in mice 12–18 months after 3-Gy whole-body irradiation. We found radiation-associated increases in peripheral blood myeloid cells and red blood cell distribution width (RDW). Deep sequencing of bone marrow and non-hematopoietic tissue cells revealed recurrent somatic mutations specifically in the hematopoietic system in 11 of 12 irradiated mice but none in 6 non-irradiated mice. The irradiated mice possessed mutations with variant allele frequencies (VAFs) of > 0.02 on an average of 5.8 per mouse; mutations with VAFs of > 0.1 and/or deletion were prevalent. Examining hematopoietic stem/progenitor cells in two irradiated mice revealed several mutations co-existing in the same clones and multiple independent clones that deliver 60–80% of bone marrow nuclear cells. Our results indicate development of massive CH due to radiation exposure. Moreover, we have characterized mutations in radiation-induced CH.

Noncancer Effects of Ionizing Radiation Exposure on the Eye, the Circulatory System and beyond: Developments made since the 2011 ICRP Statement on Tissue Reactions

“…whether radiogenic DCS involves clonal hematopoiesis of indeterminate potential (CHIP, clonal expansion of somatic mutations in hematopoietic stem cells) (293)(294)(295). For cataracts, it may be possible that there are several etiologically different subtypes, e.g., early onset PSC cataracts with evident threshold (e.g., attributable to excess LEC proliferation), late onset PSC cataracts with no clear threshold (e.g., attributable to LEC cell death and inactivation), and late onset cortical or nuclear cataracts with no clear threshold (e.g., attributable to the increased cataractogenic load that accelerates age-related changes) (Fig.…”

“…Lack of evident threshold raises a question of whether such noncancer effects are of stochastic nature: to address this question, not only the epidemiologically determined shape of the dose response curve, but also the biologically determined mechanisms would be pivotal. Mechanistic studies directly pertaining to this question may involve, but not limited to, studies that investigate whether an irradiated single lens stem cell can form a cloudy lens-like structure called lentoid ( 242 ), and whether radiogenic DCS involves clonal hematopoiesis of indeterminate potential (CHIP, clonal expansion of somatic mutations in hematopoietic stem cells) ( 293 – 295 ). For cataracts, it may be possible that there are several etiologically different subtypes, e.g., early onset PSC cataracts with evident threshold (e.g., attributable to excess LEC proliferation), late onset PSC cataracts with no clear threshold (e.g., attributable to LEC cell death and inactivation), and late onset cortical or nuclear cataracts with no clear threshold (e.g., attributable to the increased cataractogenic load that accelerates age-related changes) (Fig.…”