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Spi1 R235C point mutation confers hypersensitivity to radiation-induced acute myeloid leukemia in mice
Natalie Brown1, Rosemary Finnon1, Paul Finnon1
1Cancer Mechanisms and Biomarkers Group Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, 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 (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.
Insights
Ionizing radiation exposure accelerates acute myeloid leukemia (AML) development in mice with a Spi1 gene mutation. Biallelic Spi1 mutation is required for AML, and human SPI1/PU.1 variations may increase radiation susceptibility.
Area of Science:
- Hematology
- Oncology
- Radiation Biology
Background:
- Ionizing radiation (IR) is a known risk factor for acute myeloid leukemia (AML).
- Murine models of radiation-induced AML (rAML) involve chromosome 2 deletions and Spi1 gene point mutations.
- The Spi1 gene, also known as PU.1, is crucial for hematopoietic regulation.
Purpose of the Study:
- To investigate the role of Spi1 gene mutations in AML development and susceptibility to IR.
- To determine if a single Spi1 modification is sufficient for initiating AML.
- To explore the potential impact of human SPI1/PU.1 polymorphisms on IR susceptibility.
Main Methods:
- Generation of heterozygous CBA Spi1 R235 mutant mice (CBA^Spm/+) for AML studies.
- Assessment of AML incidence and latency in irradiated and non-irradiated mice.
- Analysis of Spi1 gene expression and chromosome 2 deletions in AML development.
Main Results:
- CBA^Spm/+ mice developed de novo AML with 100% incidence by 12 months, with latency reduced by X-irradiation in a dose-dependent manner.
- AML development was accelerated by IR exposure, supporting a two-hit mechanism.
- Biallelic Spi1 mutation, involving a second hit like chromosome 2 deletion, was required for AML.
- Spi1 haploinsufficiency was compensated by increased gene expression in reporter mice.
Conclusions:
- A single Spi1 modification can initiate AML development with complete penetrance, accelerated by IR.
- Biallelic Spi1 mutation is necessary for AML development.
- Human SPI1/PU.1 polymorphisms may confer increased susceptibility to IR, relevant for medical and environmental exposures.
