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

Graínne O'Brien, Lourdes Cruz-Garcia, Joanna Zyla, Natalie Brown, Rosemary Finnon, Joanna Polanska, Christophe Badie*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1104-1112
Number of pages9
JournalCarcinogenesis
Volume41
Issue number8
DOIs
Publication statusPublished - 1 Aug 2020

Bibliographical note

Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press.

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