Spi1 R235C point mutation confers hypersensitivity to radiation-induced acute myeloid leukemia in mice
Natalie Brown,
Rosemary Finnon,
Paul Finnon,
Roisin McCarron,
Lourdes Cruz-Garcia,
Grainne O’Brien,
Eleanor Herbert,
Cheryl L. Scudamore,
Edouard Morel,
Christophe Badie
Affiliations
Natalie Brown
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK
Rosemary Finnon
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK; Corresponding author
Paul Finnon
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK
Roisin McCarron
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK
Lourdes Cruz-Garcia
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK
Grainne O’Brien
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK
Eleanor Herbert
The Royal Veterinary College, Hatfield, Herts AL9 7TA, UK
Cheryl L. Scudamore
Mary Lyon Centre, MRC Harwell, Oxfordshire OX11 0RD, UK
Edouard Morel
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK
Christophe Badie
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK; Corresponding author
Summary: Ionizing radiation (IR) is a risk factor for acute myeloid leukemia (rAML). Murine rAMLs feature both hemizygous chromosome 2 deletions (Del2) and point mutations (R235) within the hematopoietic regulatory gene Spi1. We generated a heterozygous CBA Spi1 R235 mouse (CBASpm/+) which develops de novo AML with 100% incidence by ∼12 months old and shows a dose-dependent reduction in latency following X-irradiation. These effects are reduced on an AML-resistant C57Bl6 genetic background. CBASpm/Gfp reporter mice show increased Gfp expression, indicating compensation for Spm-induced Spi1 haploinsufficiency. Del2 is always detected in both de novo and rAMLs, indicating that biallelic Spi1 mutation is required for AML. CBASpm/+ mice show that a single Spm modification is sufficient for initiating AML development with complete penetrance, via the “two-hit” mechanism and this is accelerated by IR exposure. Similar SPI1/PU.1 polymorphisms in humans could potentially lead to enhanced susceptibility to IR following medical or environmental exposure.
