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Los genes del reloj circadiano central regulan las células madre de la leucemia en la LMA

Rishi V Puram¹, Monika S Kowalczyk², Carl G de Boer²

¹Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.

|April 9, 2016

Resumen

Los genes centrales del reloj circadiano, Clock y Bmal1, son esenciales para el crecimiento celular de la leucemia mieloide aguda (LMA). La alteración de estos genes detiene la progresión de la leucemia y agota las células madre de la leucemia (CEL).

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Área de la Ciencia:

Hematología
Biología molecular
Cronología

Sus antecedentes:

Las células madre de la leucemia (CML) impulsan la leucemia mieloide aguda (LMA) y son objetivos terapéuticos cruciales.
La identificación de genes esenciales para la supervivencia y la proliferación de LSC es clave para desarrollar terapias curativas de LMA.

Objetivo del estudio:

Identificar los factores esenciales de transcripción (TF) para la función de las células madre de la leucemia (LSC) en la leucemia mieloide aguda (AML).
Investigar el papel del reloj circadiano en la patogénesis de la LMA y el mantenimiento de la LSC.

Principales métodos:

Se utilizaron pruebas de interferencia de ARN (RNAi) conjuntas in vivo en un modelo de LMA murina.
Analizó la función de los genes identificados en la proliferación celular de la LMA, la diferenciación y el agotamiento de la LSC.
Se emplearon modelos genéticos de nocaut para evaluar la dependencia específica de la leucemia en la vía circadiana.

Principales resultados:

Se identificaron los factores de transcripción del ritmo circadiano, Clock y Bmal1, como esenciales para el crecimiento de células de LMA in vitro e in vivo.
Se demostró que la interrupción de los componentes de la vía circadiana central ejerce efectos antileucémicos, incluida la proliferación alterada, la diferenciación mieloide mejorada y el agotamiento de la LSC.
Se confirmó que las células hematopoyéticas normales y malignas poseen relojes circadianos funcionales, pero la LMA exhibe una dependencia específica de esta vía.

Conclusiones:

Los genes centrales del reloj circadiano juegan un papel crítico en la biología y la propagación de la leucemia mieloide aguda.
La vía circadiana representa una vulnerabilidad terapéutica potencial en la LMA, que ofrece nuevas vías para el desarrollo de tratamientos.