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

doi:10.1016/j.isci.2023.107530

Spi1 R235C point mutation confers hypersensitivity to radiation-induced acute myeloid leukemia in mice

iScience. 2023 Aug 3;26(9):107530. doi: 10.1016/j.isci.2023.107530. eCollection 2023 Sep 15.

Affiliations

¹ Cancer Mechanisms and Biomarkers Group Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK.
² The Royal Veterinary College, Hatfield, Herts AL9 7TA, UK.
³ Mary Lyon Centre, MRC Harwell, Oxfordshire OX11 0RD, UK.

Abstract

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 (CBA^Spm/+) 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. CBA^Spm/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. CBA^Spm/+ 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.

Keywords: Cancer; Genetics; Molecular Genetics.