Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation

Leta S. Steffen, Jeffery W. Bacher, Yuanlin Peng, Phuong N. Le, Liang Hao Ding, Paula C. Genik, F. Andrew Ray, Joel S. Bedford, Christina M. Fallgren, Susan M. Bailey, Robert L. Ullrich, Michael M. Weil, Michael D. Story

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML.

Original languageEnglish (US)
Pages (from-to)71-79
Number of pages9
JournalMutagenesis
Volume28
Issue number1
DOIs
StatePublished - Jan 2013
Externally publishedYes

Fingerprint

Gamma Rays
Linear Energy Transfer
Acute Myeloid Leukemia
Gamma rays
Energy transfer
Irradiation
Ions
Radiation
Microsatellite Repeats
Microsatellite Instability
Leukemia
Heavy Ion Radiotherapy
Heavy Ions
Space Flight
Chromosomal Instability
Mutation
Chromatids
Comparative Genomic Hybridization
Radiotherapy
Aberrations

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Steffen, L. S., Bacher, J. W., Peng, Y., Le, P. N., Ding, L. H., Genik, P. C., ... Story, M. D. (2013). Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation. Mutagenesis, 28(1), 71-79. https://doi.org/10.1093/mutage/ges055

Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation. / Steffen, Leta S.; Bacher, Jeffery W.; Peng, Yuanlin; Le, Phuong N.; Ding, Liang Hao; Genik, Paula C.; Ray, F. Andrew; Bedford, Joel S.; Fallgren, Christina M.; Bailey, Susan M.; Ullrich, Robert L.; Weil, Michael M.; Story, Michael D.

In: Mutagenesis, Vol. 28, No. 1, 01.2013, p. 71-79.

Research output: Contribution to journalArticle

Steffen, LS, Bacher, JW, Peng, Y, Le, PN, Ding, LH, Genik, PC, Ray, FA, Bedford, JS, Fallgren, CM, Bailey, SM, Ullrich, RL, Weil, MM & Story, MD 2013, 'Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation', Mutagenesis, vol. 28, no. 1, pp. 71-79. https://doi.org/10.1093/mutage/ges055
Steffen, Leta S. ; Bacher, Jeffery W. ; Peng, Yuanlin ; Le, Phuong N. ; Ding, Liang Hao ; Genik, Paula C. ; Ray, F. Andrew ; Bedford, Joel S. ; Fallgren, Christina M. ; Bailey, Susan M. ; Ullrich, Robert L. ; Weil, Michael M. ; Story, Michael D. / Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation. In: Mutagenesis. 2013 ; Vol. 28, No. 1. pp. 71-79.
@article{9c208cbeff8c4ab2b2df8e694d47b1d0,
title = "Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation",
abstract = "Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88{\%} of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42{\%} of all rAML samples, and 89{\%} of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML.",
author = "Steffen, {Leta S.} and Bacher, {Jeffery W.} and Yuanlin Peng and Le, {Phuong N.} and Ding, {Liang Hao} and Genik, {Paula C.} and Ray, {F. Andrew} and Bedford, {Joel S.} and Fallgren, {Christina M.} and Bailey, {Susan M.} and Ullrich, {Robert L.} and Weil, {Michael M.} and Story, {Michael D.}",
year = "2013",
month = "1",
doi = "10.1093/mutage/ges055",
language = "English (US)",
volume = "28",
pages = "71--79",
journal = "Mutagenesis",
issn = "0267-8357",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation

AU - Steffen, Leta S.

AU - Bacher, Jeffery W.

AU - Peng, Yuanlin

AU - Le, Phuong N.

AU - Ding, Liang Hao

AU - Genik, Paula C.

AU - Ray, F. Andrew

AU - Bedford, Joel S.

AU - Fallgren, Christina M.

AU - Bailey, Susan M.

AU - Ullrich, Robert L.

AU - Weil, Michael M.

AU - Story, Michael D.

PY - 2013/1

Y1 - 2013/1

N2 - Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML.

AB - Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML.

UR - http://www.scopus.com/inward/record.url?scp=84871782093&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871782093&partnerID=8YFLogxK

U2 - 10.1093/mutage/ges055

DO - 10.1093/mutage/ges055

M3 - Article

C2 - 22987027

AN - SCOPUS:84871782093

VL - 28

SP - 71

EP - 79

JO - Mutagenesis

JF - Mutagenesis

SN - 0267-8357

IS - 1

ER -