Kras mutations and PU.1 promoter methylation are new pathways in murine radiation-induced AML.
Carcinogenesis
; 41(8): 1104-1112, 2020 08 12.
Article
en En
| MEDLINE
| ID: mdl-31646336
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
/
Leucemia Experimental
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Leucemia Inducida por Radiación
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Regulación Leucémica de la Expresión Génica
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Transactivadores
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Proteínas Proto-Oncogénicas p21(ras)
/
Proteínas Proto-Oncogénicas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Carcinogenesis
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido