Genetic instability in radiation-induced leukaemias: mouse models

Abstract

Studies of mouse radiation-induced leukaemias have detected evidence of genetic instability. However, with few exceptions, most of this instability was also observed during de novo multi-stage carcinogenesis. This raises the possibility that radiation induces ongoing genetic instability that is functionally indistinguishable to that implicated in de novo tumour progression.

Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia

“…Several studies have provided circumstantial evidence that radiation can induce AML-type deletions of chromosome 2 (Hayata, 1985;Trakhtenbrot et al, 1988;Ban et al, 1997;Peng et al, 2009), even though it is inconclusive whether the aberrations arise as a consequence of initial DNA damage or through delayed chromosomal instability (Plumb et al, 1998;Bouffler et al, 2001;Boulton et al, 2001). As for the mutation of Sfpi1, however, there is no direct data about the involvement of radiation in its induction.…”

The absence of significant mutational events of the p53 gene in the only two salivary gland tumors possessing radiation-related development risks, mucoepidermoid carcinoma and Warthin tumor

“…Our previous studies showed that these tumors developed after long intervals since irradiation by the atomic bombs, although their occurrences were highly dependent on the radiation doses of the patients (14-15). These two tumors are hence typical but rare examples of human diseases caused by delayed gene alterations due to radiation-induced genetic instability (45)(46). It is unknown whether the molecular mechanisms for such gene alterations develop after a long interval from irradiation events.…”

True

“…[13][14][15][16][17] In the mouse, molecular genetic analyses of radiationinduced thymic lymphomas (TL) revealed a 45-66% chromosome 4 LOH incidence, and identified three commonly deleted regions (thymic lymphoma suppressor regions 1-3, TLSR1-3) within a 30 cM interval. [18][19][20] frequently detected in radiation-induced TLs (42% and 15% respectively). 1 However, chromosome 4 LOH in mouse radiation-induced TLs is mouse strain dependent as TLs which arose in a (BALB/c × MSM) genetic background have a negligible LOH incidence 21 compared to the LOH incidence in TLs which arose in (C57BL/6 × RF/J)F1 or (C57BL/6 × CBA/H) genetic backgrounds.…”

“…1 However, chromosome 4 LOH in mouse radiation-induced TLs is mouse strain dependent as TLs which arose in a (BALB/c × MSM) genetic background have a negligible LOH incidence 21 compared to the LOH incidence in TLs which arose in (C57BL/6 × RF/J)F1 or (C57BL/6 × CBA/H) genetic backgrounds. 18,19 We recently detected a 45% incidence of chromosome 4 LOH in 3 Gy X-ray-induced mouse acute myeloid leukaemias (AMLs) as well as a 66% incidence in TLs. 19 Whilst mouse TLs are generally induced as a consequence of a fractionated dose of X-rays, 18,21 in our study, (CBA/H × C57BL/6)F1 backcross and intercross mice were exposed to a single acute X-ray dose.…”

“…18,19 We recently detected a 45% incidence of chromosome 4 LOH in 3 Gy X-ray-induced mouse acute myeloid leukaemias (AMLs) as well as a 66% incidence in TLs. 19 Whilst mouse TLs are generally induced as a consequence of a fractionated dose of X-rays, 18,21 in our study, (CBA/H × C57BL/6)F1 backcross and intercross mice were exposed to a single acute X-ray dose. As CBA/H mice are susceptible to radiationinduced AML, and C57BL/6 mice are susceptible to radiationinduced TL, 22,23 AMLs and TLs were generated in a similar genetic background as a consequence of the same initiating event.…”