Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.
Cancer Cell
; 36(2): 123-138.e10, 2019 08 12.
Article
em En
| MEDLINE
| ID: mdl-31303423
ABSTRACT
Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cromossomos Humanos Par 21
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Biomarcadores Tumorais
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Leucemia Mieloide
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Transformação Celular Neoplásica
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Síndrome de Down
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Fator de Transcrição GATA1
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Subunidade beta Comum dos Receptores de Citocinas
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Reação Leucemoide
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Mutação
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Cell
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Alemanha