RESUMEN
NOTCH1 pathway activation contributes to the pathogenesis of over 60% of T-cell acute lymphoblastic leukemia (T-ALL). While Notch is thought to exert the majority of its effects through transcriptional activation of Myc, it also likely has independent roles in T-ALL malignancy. Here, we utilized a zebrafish transgenic model of T-ALL, where Notch does not induce Myc transcription, to identify a novel Notch gene expression signature that is also found in human T-ALL and is regulated independently of Myc. Cross-species microarray comparisons between zebrafish and mammalian disease identified a common T-ALL gene signature, suggesting that conserved genetic pathways underlie T-ALL development. Functionally, Notch expression induced a significant expansion of pre-leukemic clones; however, a majority of these clones were not fully transformed and could not induce leukemia when transplanted into recipient animals. Limiting-dilution cell transplantation revealed that Notch signaling does not increase the overall frequency of leukemia-propagating cells (LPCs), either alone or in collaboration with Myc. Taken together, these data indicate that a primary role of Notch signaling in T-ALL is to expand a population of pre-malignant thymocytes, of which a subset acquire the necessary mutations to become fully transformed LPCs.
Asunto(s)
Transformación Celular Neoplásica , Regulación Leucémica de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptor Notch1/fisiología , Animales , Animales Modificados Genéticamente , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Línea Celular Tumoral , Proliferación Celular , Perfilación de la Expresión Génica , Humanos , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Timocitos , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
Classic stem cell biology approaches tailored specifically with lung biology in mind are needed to bring the field of lung stem cell biology up to speed with that in other tissues. The infrequent cellular turnover, the diversity of cell types, and the necessity of daily cell function in this organ must be considered in stem cell studies. Previous work has created a base from which to explore transplantation, label retention, and more sophisticated lineage-tracing schemes to identify and characterize stem cell populations in the normal lung. These approaches are also imperative for building on precedents set in other tissues in the exploration of the cancer stem cell hypothesis in lung cancers. Additionally, recent studies provide key leads to further explore the molecular mechanisms that regulate lung homeostasis. Here, we discuss strategies to advance the field of lung stem cell biology with an emphasis on developing new, lung-specific tools.
