Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia.
Sci Transl Med
; 4(149): 149ra118, 2012 Aug 29.
Article
en En
| MEDLINE
| ID: mdl-22932223
ABSTRACT
Given that most bone marrow cells are short-lived, the accumulation of multiple leukemogenic mutations in a single clonal lineage has been difficult to explain. We propose that serial acquisition of mutations occurs in self-renewing hematopoietic stem cells (HSCs). We investigated this model through genomic analysis of HSCs from six patients with de novo acute myeloid leukemia (AML). Using exome sequencing, we identified mutations present in individual AML patients harboring the FLT3-ITD (internal tandem duplication) mutation. We then screened the residual HSCs and detected some of these mutations including mutations in the NPM1, TET2, and SMC1A genes. Finally, through single-cell analysis, we determined that a clonal progression of multiple mutations occurred in the HSCs of some AML patients. These preleukemic HSCs suggest the clonal evolution of AML genomes from founder mutations, revealing a potential mechanism contributing to relapse. Such preleukemic HSCs may constitute a cellular reservoir that should be targeted therapeutically for more durable remissions.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Preleucemia
/
Células Madre Neoplásicas
/
Células Madre Hematopoyéticas
/
Leucemia Mieloide Aguda
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Proliferación Celular
/
Evolución Clonal
/
Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Transl Med
Asunto de la revista:
CIENCIA
/
MEDICINA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos