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Kras mutations and PU.1 promoter methylation are new pathways in murine radiation-induced AML.

Authors
  • O'Brien, Gráinne1
  • Cruz-Garcia, Lourdes1
  • Zyla, Joanna2
  • Brown, Natalie1
  • Finnon, Rosemary1
  • Polanska, Joanna2
  • Badie, Christophe1
  • 1 Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Oxfordshire, UK.
  • 2 Silesian University of Technology, Data Mining Division, Gliwice, Poland. , (Poland)
Type
Published Article
Journal
Carcinogenesis
Publisher
Oxford University Press
Publication Date
Aug 12, 2020
Volume
41
Issue
8
Pages
1104–1112
Identifiers
DOI: 10.1093/carcin/bgz175
PMID: 31646336
Source
Medline
Language
English
License
Unknown

Abstract

Therapy-related and more specifically radiotherapy-associated acute myeloid leukaemia (AML) is a well-recognized potential complication of cytotoxic therapy for the treatment of a primary cancer. The CBA mouse model is used to study radiation leukaemogenesis mechanisms with Sfpi1/PU.1 deletion and point mutation already identified as driving events during AML development. To identify new pathways, we analysed 123 mouse radiation-induced AML (rAML) samples for the presence of mutations identified previously in human AML and found three genes to be mutated; Sfpi1 R235 (68%), Flt3-ITD (4%) and Kras G12 (3%), of which G12R was previously unreported. Importantly, a significant decrease in Sfpi1 gene expression is found almost exclusively in rAML samples without an Sfpi1 R235 mutation and is specifically associated with up-regulation of mir-1983 and mir-582-5p. Moreover, this down-regulation of Sfpi1 mRNA is negatively correlated with DNA methylation levels at specific CpG sites upstream of the Sfpi1 transcriptional start site. The down regulation of Sfpi1/PU.1 has also been reported in human AML cases revealing one common pathway of myeloid disruption between mouse and human AML where dysregulation of Sfpi1/PU.1 is a necessary step in AML development. © The Author(s) 2019. Published by Oxford University Press.

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