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

• Published in: Scientific reports Vol. 12; no. 1; pp. 17276 - 11
• Main Authors: Yoshida, Kengo, Satoh, Yasunari, Uchimura, Arikuni, Misumi, Munechika, Kyoizumi, Seishi, Taga, Masataka, Matsuda, Yukiko, Noda, Asao, Kusunoki, Yoichiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.10.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/737; 631/250/232; Animals; Bone marrow; Bone Marrow - radiation effects; Bone Marrow Cells; Cardiovascular diseases; Clone Cells; Erythrocytes; Gene deletion; Gene frequency; Hematopoiesis - genetics; Hematopoiesis - radiation effects; Hematopoietic stem cells; Hematopoietic Stem Cells - pathology; Humanities and Social Sciences; Irradiation; Malignancy; Mice; multidisciplinary; Mutation; Myeloid cells; Peripheral blood; Progenitor cells; Radiation; Science; Science & Technology - Other Topics; Science (multidisciplinary); Whole-Body Irradiation - adverse effects; X-rays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-21621-6

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.