| First Author | O'Brien G | Year | 2020 |
| Journal | Carcinogenesis | Volume | 41 |
| Issue | 8 | Pages | 1104-1112 |
| PubMed ID | 31646336 | Mgi Jnum | J:296247 |
| Mgi Id | MGI:6466781 | Doi | 10.1093/carcin/bgz175 |
| Citation | O'Brien G, et al. (2020) Kras mutations and PU.1 promoter methylation are new pathways in murine radiation-induced AML. Carcinogenesis 41(8):1104-1112 |
| abstractText | 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. |
