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1.
Sci Rep ; 11(1): 7288, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33790356

RESUMEN

Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for patients. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML in adults by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the epigenetic mechanism underpinning the enhanced self-renewal conferred by cohesin-haploinsufficiency. First, given the substantial difference in the mutational spectrum between pediatric and adult AML patients, we first sought to identify if HOXA9 was also elevated in children. Next, using primary HSPCs as a model we demonstrate that abnormal self-renewal due to cohesin loss is blocked by DOT1L inhibition. In cohesin-depleted cells, DOT1L inhibition is associated with H3K79me2 depletion and a concomitant increase in H3K27me3. Importantly, we find that there are cohesin-dependent gene expression changes that promote a leukemic profile, including HoxA overexpression, that are preferentially reversed by DOT1L inhibition. Our data further characterize how cohesin mutations contribute to AML development, identifying DOT1L as a potential therapeutic target for adult and pediatric AML patients harboring cohesin mutations.


Asunto(s)
Proteínas de Ciclo Celular/genética , Autorrenovación de las Células , Proteínas Cromosómicas no Histona/genética , Células Madre Hematopoyéticas/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Leucemia Mieloide Aguda/metabolismo , Animales , Bencimidazoles/farmacología , Proteínas de Ciclo Celular/deficiencia , Células Cultivadas , Proteínas Cromosómicas no Histona/deficiencia , Inhibidores Enzimáticos/farmacología , Epigénesis Genética , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/fisiología , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Ratones , Cohesinas
2.
J Med Chem ; 61(11): 4720-4738, 2018 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-29741891

RESUMEN

Estrogen receptor-beta (ERß) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERß agonists (SERBAs) with in vivo efficacy that are A-C estrogens, lacking the B and D estrogen rings. The most potent and selective A-C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the ß over α isoform and with EC50s of 20-30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound's ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A-C estrogen is selective, brain penetrant, and facilitates memory consolidation.


Asunto(s)
Receptor beta de Estrógeno/agonistas , Estrógenos/química , Estrógenos/farmacología , Consolidación de la Memoria/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/metabolismo , Estrógenos/metabolismo , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Conformación Proteica , Relación Estructura-Actividad
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