Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations.
Elife
; 52016 11 23.
Article
em En
| MEDLINE
| ID: mdl-27879203
The FLT3 Internal Tandem Duplication (FLT3ITD) mutation is common in adult acute myeloid leukemia (AML) but rare in early childhood AML. It is not clear why this difference occurs. Here we show that Flt3ITD and cooperating Flt3ITD/Runx1 mutations cause hematopoietic stem cell depletion and myeloid progenitor expansion during adult but not fetal stages of murine development. In adult progenitors, FLT3ITD simultaneously induces self-renewal and myeloid commitment programs via STAT5-dependent and STAT5-independent mechanisms, respectively. While FLT3ITD can activate STAT5 signal transduction prior to birth, this signaling does not alter gene expression until hematopoietic progenitors transition from fetal to adult transcriptional states. Cooperative interactions between Flt3ITD and Runx1 mutations are also blunted in fetal/neonatal progenitors. Fetal/neonatal progenitors may therefore be protected from leukemic transformation because they are not competent to express FLT3ITD target genes. Changes in the transcriptional states of developing hematopoietic progenitors may generally shape the mutation spectra of human leukemias.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
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Leucemia Mieloide Aguda
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Regulação Leucêmica da Expressão Gênica
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Tirosina Quinase 3 Semelhante a fms
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Subunidade alfa 2 de Fator de Ligação ao Core
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Células-Tronco Fetais
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article