R235C Point Mutation Confers Hypersensitivity to Radiation-induced Acute Myeloid Leukemia in Mice

Overview

Journal iScience

Publisher Cell Press

Date 2023 Sep 4

PMID 37664628

Authors

Natalie Brown

Rosemary Finnon

Paul Finnon

Roisin McCarron

Lourdes Cruz-Garcia

Grainne OBrien

Eleanor Herbert

Cheryl L Scudamore

Edouard Morel

Christophe Badie

Affiliations

Soon will be listed here.

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 . We generated a heterozygous CBA R235 mouse (CBA) which develops 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 reporter mice show increased Gfp expression, indicating compensation for Spm-induced haploinsufficiency. Del2 is always detected in both and rAMLs, indicating that biallelic Spi1 mutation is required for AML. CBA 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 polymorphisms in humans could potentially lead to enhanced susceptibility to IR following medical or environmental exposure.

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