Kras mutations and PU.1 promoter methylation are new pathways in murine radiation-induced AML
In: Carcinogenesis, Jg. 41 (2019-10-24), S. 1104-1112
Online
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Zugriff:
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.
This work identifies new leukaemia pathways involving genetic and epigenetic changes after irradiation exposure.
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Kras mutations and PU.1 promoter methylation are new pathways in murine radiation-induced AML
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Autor/in / Beteiligte Person: | Finnon, Rosemary ; Badie, Christophe ; O’Brien, Grainne ; Brown, Natalie ; Polanska, Joanna ; Zyla, Joanna ; Cruz-Garcia, Lourdes |
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Zeitschrift: | Carcinogenesis, Jg. 41 (2019-10-24), S. 1104-1112 |
Veröffentlichung: | Oxford University Press (OUP), 2019 |
Medientyp: | unknown |
ISSN: | 1460-2180 (print) ; 0143-3334 (print) |
DOI: | 10.1093/carcin/bgz175 |
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