SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment.
Nat Commun
; 6: 10004, 2015 Dec 08.
Article
en En
| MEDLINE
| ID: mdl-26643973
ABSTRACT
Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34(+)CD38(-)CD45RA(-)CD90(+)CD49f(+) HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
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Médula Ósea
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Síndromes Mielodisplásicos
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Células Madre Hematopoyéticas
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Leucemia Mieloide Aguda
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Transformación Celular Neoplásica
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Ribonucleoproteína Nuclear Pequeña U2
Límite:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Reino Unido