Microsatellite analysis of recurrent chromosome 2 deletions in acute myeloid leukaemia induced by radiation in FI hybrid mice

Clark, Debbie; Meijne, Emmy; Bouffler, Simon; Huiskamp, R.; Skidmore, Christopher J.; Cox, Roger; Silver, Andrew

doi:10.1002/(sici)1098-2264(199608)16:4<238::aid-gcc3>3.0.co;2-z

Cited by 27 publications

(11 citation statements)

References 30 publications

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“…The incidence increases with doses up to 3 Gy and the symptoms of the affected mice are similar to those found in human AML (Upton et al, 1958;Major, 1979;Mole et al, 1983;Resnitzky et al, 1985;Seki et al, 1991). The leukaemic cells usually carry a deletion of chromosome 2 (Hayata et al, 1983;Trakhtenbrot et al, 1988;Rithidech et al, 1993;Clark et al, 1996) and a mutation of the Sfpi1 gene on the retained homologue (Cook et al, 2004;Suraweera et al, 2005;Hirouchi et al, 2008). These genetic changes result in downregulation of the transcript PU.1, which is crucial for normal myeloid differentiation (Cook et al, 2004).…”

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confidence: 75%

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

Ban

Kai

2009

Br J Cancer

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BACKGROUND: The essential aetiology of radiation-induced acute myeloid leukaemia (AML) in mice is the downregulation of the transcription factor PU.1. The causative mutation of the PU.1-endocing Sfpi1 gene consists mostly of C:G to T:A transitions at a CpG site and is likely to be of spontaneous origin. To work out a mechanism underlying the association between radiation exposure and the AML induction, we have hypothesised that replicative stress after irradiation accelerates the ageing of haematopoietic stem cells (HSCs), and the ageing-related decline in DNA repair could affect the spontaneous mutation rates. METHODS: Mathematical model analysis was conducted to examine whether and to what extent the cell kinetics of HSCs can be modified after irradiation. The haematopoietic differentiation process is expressed as a mathematical model and the cell-kinetics parameters were estimated by fitting the simulation result to the assay data. RESULTS: The analysis revealed that HSCs cycle vigourously for more than a few months after irradiation. The estimated number of cell divisions per surviving HSC in 3 Gy-exposed mice reached as high as ten times that of the unexposed. INTERPRETATION: The mitotic load after 3 Gy irradiation seems to be heavy enough to accelerate the ageing of HSCs and the hypothesis reasonably explains the leukaemogenic process.

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confidence: 75%

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

Ban

Kai

2009

Br J Cancer

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“…No host spleen tissue contamination was found for any of the day 11 CFU-S-derived clones analysed. (5) Titration curve: Preliminary PCR titration studies were carried out using increasing amount of either CBA/H or C57BL/6 gDNA to check for equal amplification of the two alleles during the PCR as it been reported 33,34 that PCR amplification of some microsatellite markers would not yield equal amplification of the two alleles. This bias towards a stronger amplification of one allele can lead to misinterpretation (ie scoring of allelic imbalance) when gDNA concentration is very low or suboptimal PCR conditions are used.…”

Section: Validation Of the Polymorphic Microsatellite Markers Analysementioning

confidence: 99%

A PCR-based clonal analysis of radiation-induced loss of heterozygosity in haemopoietic stem cells

Rigat

Lorimore

et al. 2001

Leukemia

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“…(b) Schematic representation of the hydrogen bonds (solid lines) and the van der Waal interactions (dashed lines) between the a3 helix of PU.1 and the target DNA containing the recognition sequence GGAA Mutations of the PU.1 Ets domain N Suraweera et al Overall, the mouse data indicate a highly specific mechanism of myeloid leukaemogenesis possibly driven by loss of one PU.1 copy. This event may itself be unique to the mouse and might relate to the radiationsensitive proximal and distal breakpoint cluster regions that have been identified and mapped on chromosome 2 (Clark et al, 1996;Silver et al, 1999;Finnon et al, 2002). The juxtaposing of these fragile domains in time and space within the interphase nuclei of precursor bone marrow cells would be expected to promote site-specific postirradiation chromosomal interaction, leading to interstitial loss of a significant proportion of one copy of mouse chromosome 2 that includes the PU.1 locus (Silver et al, 1999).…”

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confidence: 99%

Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia

Suraweera

Meijne

Moody³

et al. 2005

Oncogene

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Murine radiation-induced acute myeloid leukaemia (AML) is characterized by loss of one copy of chromosome 2. Previously, we positioned the critical haematopoietic-specific transcription factor PU.1 within a minimally deleted region. We now report a high frequency (>65%) of missense mutation at codon 235 in the DNAbinding Ets domain of PU.1 in murine AML. Earlier studies, outside the context of malignancy, determined that conversion of arginine 235 (R235) to any other amino-acid residue leads to ablation of DNA-binding function and loss of expression of downstream targets. We show that mutation of R235 does not lead to protein loss, and occurs specifically in those AMLs showing loss of one copy of PU.1 (P ¼ 0.001, Fisher's exact test). PU.1 mutations were not found in the coding region, UTRs or promoter of human therapy-related AMLs. Potentially regulatory elements upstream of PU.1 were located but no mutations found. In conclusion, we have identified the cause of murine radiation-induced AML and have shown that loss of one copy of PU.1, as a consequence of flanking radiation-sensitive fragile domains on chromosome 2, and subsequent R235 conversion are highly specific to this mouse model. Such a mechanism does not operate, or is extremely rare, in human AML.

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Microsatellite analysis of recurrent chromosome 2 deletions in acute myeloid leukaemia induced by radiation in FI hybrid mice

Cited by 27 publications

References 30 publications

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

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

A PCR-based clonal analysis of radiation-induced loss of heterozygosity in haemopoietic stem cells

Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia

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