AMKL chimeric transcription factors are potent inducers of leukemia.
Leukemia
; 31(10): 2228-2234, 2017 10.
Article
en En
| MEDLINE
| ID: mdl-28174417
ABSTRACT
Acute megakaryoblastic leukemia in patients without Down syndrome is a rare malignancy with a poor prognosis. RNA sequencing of fourteen pediatric cases previously identified novel fusion transcripts that are predicted to be pathological including CBFA2T3-GLIS2, GATA2-HOXA9, MN1-FLI and NIPBL-HOXB9. In contrast to CBFA2T3-GLIS2, which is insufficient to induce leukemia, we demonstrate that the introduction of GATA2-HOXA9, MN1-FLI1 or NIPBL-HOXB9 into murine bone marrow induces overt disease in syngeneic transplant models. With the exception of MN1, full penetrance was not achieved through the introduction of fusion partner genes alone, suggesting that the chimeric transcripts possess a unique gain-of-function phenotype. Leukemias were found to exhibit elements of the megakaryocyte erythroid progenitor gene expression program, as well as unique leukemia-specific signatures that contribute to transformation. Comprehensive genomic analyses of resultant murine tumors revealed few cooperating mutations confirming the strength of the fusion genes and their role as pathological drivers. These models are critical for both the understanding of the biology of disease as well as providing a tool for the identification of effective therapeutic agents in preclinical studies.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Leucemia Megacarioblástica Aguda
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Regulación Leucémica de la Expresión Génica
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Proteínas de Fusión Oncogénica
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Transformación Celular Neoplásica
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Leukemia
Asunto de la revista:
HEMATOLOGIA
/
NEOPLASIAS
Año:
2017
Tipo del documento:
Article