Mapping the cellular origin and early evolution of leukemia in Down syndrome.
Science
; 373(6551)2021 07 09.
Article
en En
| MEDLINE
| ID: mdl-34244384
ABSTRACT
Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Preleucemia
/
Células Madre Hematopoyéticas
/
Leucemia Mieloide
/
Síndrome de Down
/
Proteínas de Ciclo Celular
/
Factor de Transcripción GATA1
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Science
Año:
2021
Tipo del documento:
Article