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El equilibrio epigenético asegura el control mecanicista de la amplificación y el reordenamiento de la MLL

Zach H Gray¹, Damayanti Chakraborty², Reuben R Duttweiler³

¹Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

|October 3, 2023

Resumen

Los reguladores epigenéticos controlan las amplificaciones y reordenamientos de MLL/KMT2A en la leucemia. El equilibrio de metilación de la histona y la ocupación del CTCF en el locus MLL/KMT2A son claves, ofreciendo posibles objetivos farmacológicos.

Área de la Ciencia:

* Biología molecular
* La epigenética del cáncer
* Malignidades hematológicas

Sus antecedentes:

* Las amplificaciones y translocaciones de MLL/KMT2A son comunes en varias leucemias.
* Los mecanismos moleculares que impulsan estas alteraciones siguen siendo en gran medida desconocidos.
* La comprensión de estos mecanismos es crucial para desarrollar terapias dirigidas.

Objetivo del estudio:

* Para aclarar los reguladores epigenéticos que controlan las alteraciones del locus MLL/KMT2A.
* Para investigar el papel de la metilación de la histona H3 lisina 9 (H3K9me1/2) en las reorganizaciones de MLL/KMT2A.
* Para explorar el impacto de la quimioterapia, como la doxorrubicina, en estas modificaciones epigenéticas y las alteraciones de MLL/KMT2A.

Principales métodos:

* Análisis de los niveles de metilación de histonas (H3K9me1/2) en el locus MLL/KMT2A.
* Investigación de la ocupación de CTCF y su correlación con las alteraciones de MLL/KMT2A.
* Estudios de agotamiento y sobreexpresión de reguladores epigenéticos clave (KDM3B, G9a/EHMT2, CTCF) en modelos celulares y animales.
* Evaluación de los efectos de la doxorrubicina sobre los niveles de proteínas y las alteraciones de la MLL/KMT2A.

Principales resultados:

* El equilibrio H3K9me1/2 en el locus MLL/KMT2A regula las amplificaciones y reordenamientos.
* El agotamiento de KDM3B aumenta H3K9me1/2, reduce la ocupación de CTCF y promueve las alteraciones de MLL/KMT2A.
* La doxorubicina suprime el KDM3B y el CTCF, dando lugar a alteraciones de la MLL/ KMT2A, que pueden ser rescatadas por la sobreexpresión del KDM3B y el CTCF.
* La inhibición de G9a suprime los eventos de MLL/ KMT2A inducidos por la doxorubicina.

Conclusiones:

* Los reguladores epigenéticos, específicamente la interacción entre KDM3B, G9a / EHMT2 y CTCF, controlan las amplificaciones y reordenamientos de MLL / KMT2A.
* Estos mecanismos epigenéticos están implicados en la leucemia inducida por la terapia.
* Los reguladores epigenéticos identificados representan objetivos farmacológicos manejables para el tratamiento de leucemias inducidas por MLL/KMT2A.

Palabras clave:

CTCF (en inglés)Amplificación del ADN G9a y El H3K9me KDM3B (en inglés)En el caso de las PYME, se aplicarán los siguientes criterios:MLL (en inglés)Doxorubicina y sus derivados ecADN y sus derivados reorganizaciones

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