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Tracking preleukemic cells in vivo to reveal the sequence of molecular events in radiation leukemogenesis

Verbiest, T; Finnon, P; Brown, N; Cruz-Garcia, L; Finnon, P; O'Brien, G; Ross, E; Bouffler, S; Scudamore, C L; Badie, C

Authors

T Verbiest

P Finnon

N Brown

L Cruz-Garcia

P Finnon

G O'Brien

E Ross

S Bouffler

C L Scudamore

C Badie



Abstract

Epidemiological studies have demonstrated an increased leukemia incidence following ionizing radiation exposure, but to date, the target cells and underlying mechanisms of radiation leukemogenesis remain largely unidentified. We engineered a mouse model carrying a different fluorescent marker on each chromosome 2, located inside the minimum deleted region occurring after radiation exposure and recognized as the first leukemogenic event. Using this tailored model, we report that following radiation exposure, more than half of asymptomatic CBA Sfpi1GFP/mCh mice presented with expanding clones of preleukemic hematopoietic cells harboring a hemizygous interstitial deletion of chromosome 2. Moreover, following isolation of preleukemic hematopoietic stem and progenitor cells irradiated in their native microenvironment, we identified the presence of Sfpi1 point mutations within a subpopulation of these preleukemic cells expanding rapidly (increasing from 6% to 55% in 21 days in peripheral blood in one case), hence identifying for the first time the presence of such cells within a living animal. Importantly, we also report a previously undescribed gender difference in the phenotype of the preleukemic cells and leukemia, suggesting a gender imbalance in the radiation-induced leukemic target cell. In conclusion, we provide novel insights into the sequence of molecular events occurring during the (radiation-induced) leukemic clonal evolution.

Citation

Verbiest, T., Finnon, P., Brown, N., Cruz-Garcia, L., Finnon, P., O'Brien, G., …Badie, C. (2018). Tracking preleukemic cells in vivo to reveal the sequence of molecular events in radiation leukemogenesis. Nature, 32, 1435-1444. https://doi.org/10.1038/s41375-018-0085-1

Journal Article Type Article
Acceptance Date Feb 6, 2018
Publication Date Mar 3, 2018
Deposit Date Jun 12, 2018
Publicly Available Date Jun 13, 2018
Journal Nature
Print ISSN 0028-0836
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 32
Pages 1435-1444
DOI https://doi.org/10.1038/s41375-018-0085-1
Public URL https://rvc-repository.worktribe.com/output/1388278

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