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1.
Cancer Cell ; 38(4): 534-550.e9, 2020 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-32888433

RESUMEN

Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER+) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third ß strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically, Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, SY242CS shows neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome. Structural modeling predicts that SY242CS confers a conformational change that mediates stable binding to a non-canonical DNA motif. Taken together, our results provide insights into how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.


Asunto(s)
Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cromatina/genética , Factor Nuclear 3-alfa del Hepatocito/genética , Mutación Missense , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Cromatina/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 3-alfa del Hepatocito/química , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Células MCF-7 , Ratones Desnudos , Modelos Moleculares , Dominios Proteicos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
2.
Sci Rep ; 10(1): 11657, 2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32669620

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Treatments for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts TGFß signaling and suppresses myofibroblast differentiation, however practical strategies to raise tissue PGE2 during IPF have been limited. We previously described the discovery of a small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced pulmonary fibrosis (PF). Long-term PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine PF, and may have clinical utility to treat human disease.


Asunto(s)
Antiinflamatorios/farmacología , Dinoprostona/metabolismo , Inhibidores Enzimáticos/farmacología , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Piridinas/farmacología , Tiofenos/farmacología , Animales , Bleomicina/administración & dosificación , Peso Corporal/efectos de los fármacos , Dinoprostona/agonistas , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Células Endoteliales/patología , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/enzimología , Femenino , Expresión Génica , Humanos , Hidroxiprostaglandina Deshidrogenasas/genética , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/enzimología , Fibrosis Pulmonar Idiopática/mortalidad , Inflamación , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/patología , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Terapia Molecular Dirigida/métodos , Pruebas de Función Respiratoria , Análisis de Supervivencia
3.
Nat Genet ; 52(2): 198-207, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31932695

RESUMEN

Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common alterations of the SWI/SNF complex in estrogen-receptor-positive (ER+) breast cancer. We identify that ARID1A inactivating mutations are present at a high frequency in advanced endocrine-resistant ER+ breast cancer. An epigenome CRISPR-CAS9 knockout (KO) screen identifies ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A inactivation in cells and in patients leads to resistance to ER degraders by facilitating a switch from ER-dependent luminal cells to ER-independent basal-like cells. Cellular plasticity is mediated by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the luminal lineage-determining transcription factors including ER, forkhead box protein A1 (FOXA1) and GATA-binding factor 3 (GATA3). ARID1A also regulates genome-wide ER-FOXA1 chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in maintaining luminal cell identity and endocrine therapeutic response in ER+ breast cancer.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/genética , Receptores de Estrógenos/metabolismo , Factores de Transcripción/genética , Animales , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Proteínas de Unión al ADN/metabolismo , Femenino , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Factor Nuclear 3-alfa del Hepatocito/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Ratones , Mutación , Receptores de Estrógenos/genética , Factores de Transcripción/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Cancer Discov ; 10(1): 142-157, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31582374

RESUMEN

TGFß is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGFß pathway components occurs in only half of PDA cases. TGFß cooperates with oncogenic RAS signaling to trigger epithelial-to-mesenchymal transition (EMT) in premalignant pancreatic epithelial progenitors, which is coupled to apoptosis owing to an imbalance of SOX4 and KLF5 transcription factors. We report that PDAs that develop with the TGFß pathway intact avert this apoptotic effect via ID1. ID1 family members are expressed in PDA progenitor cells and encode components of a set of core transcriptional regulators shared by PDAs. PDA progression selects against TGFß-mediated repression of ID1. The sustained expression of ID1 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on ID1 to preserve its expression in PDA. Our results identify ID1 as a crucial node and potential therapeutic target in PDA. SIGNIFICANCE: Half of PDAs escape TGFß-induced tumor suppression without inactivating the TGFß pathway. We report that ID1 expression is selected for in PDAs and that ID1 uncouples TGFß-induced EMT from apoptosis. ID1 thus emerges as a crucial regulatory node and a target of interest in PDA.This article is highlighted in the In This Issue feature, p. 1.


Asunto(s)
Apoptosis , Carcinoma Ductal Pancreático/patología , Transición Epitelial-Mesenquimal , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Neoplasias Pancreáticas/patología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Proteína 1 Inhibidora de la Diferenciación/genética , Ratones , Ratones Desnudos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Factor de Crecimiento Transformador beta/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Cell Stem Cell ; 25(5): 682-696.e8, 2019 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-31495782

RESUMEN

Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Autorrenovación de las Células/genética , Cromatina/metabolismo , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Proteínas Nucleares/metabolismo , Animales , Linfocitos B/metabolismo , Proteínas de Ciclo Celular/genética , Linaje de la Célula/genética , Inmunoprecipitación de Cromatina , Regulación de la Expresión Génica/genética , Técnicas de Inactivación de Genes , Células Madre Hematopoyéticas/citología , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Proteínas Nucleares/genética , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , RNA-Seq , Mutaciones Letales Sintéticas/genética , Transactivadores/genética , Transactivadores/metabolismo
6.
Nat Genet ; 51(6): 999-1010, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31110351

RESUMEN

Human embryonic stem cells (ESCs) and human induced pluripotent stem cells hold great promise for cell-based therapies and drug discovery. However, homogeneous differentiation remains a major challenge, highlighting the need for understanding developmental mechanisms. We performed genome-scale CRISPR screens to uncover regulators of definitive endoderm (DE) differentiation, which unexpectedly uncovered five Jun N-terminal kinase (JNK)-JUN family genes as key barriers of DE differentiation. The JNK-JUN pathway does not act through directly inhibiting the DE enhancers. Instead, JUN co-occupies ESC enhancers with OCT4, NANOG, SMAD2 and SMAD3, and specifically inhibits the exit from the pluripotent state by impeding the decommissioning of ESC enhancers and inhibiting the reconfiguration of SMAD2 and SMAD3 chromatin binding from ESC to DE enhancers. Therefore, the JNK-JUN pathway safeguards pluripotency from precocious DE differentiation. Direct pharmacological inhibition of JNK significantly improves the efficiencies of generating DE and DE-derived pancreatic and lung progenitor cells, highlighting the potential of harnessing the knowledge from developmental studies for regenerative medicine.


Asunto(s)
Diferenciación Celular/genética , Endodermo/embriología , Endodermo/metabolismo , Genoma , Genómica , Sistema de Señalización de MAP Quinasas , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Línea Celular , Cromatina/genética , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Expresión Génica , Técnicas de Inactivación de Genes , Genes Reporteros , Genómica/métodos , Humanos , Células Madre Pluripotentes Inducidas , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Modelos Biológicos , Reproducibilidad de los Resultados , Proteínas Smad
7.
Cell Stem Cell ; 24(1): 153-165.e7, 2019 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-30472158

RESUMEN

Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia. IKZF2 is highly expressed in leukemic stem cells (LSCs), and its deficiency results in defective LSC function. IKZF2 depletion in acute myeloid leukemia (AML) cells reduced colony formation, increased differentiation and apoptosis, and delayed leukemogenesis. Gene expression, chromatin accessibility, and direct IKZF2 binding in MLL-AF9 LSCs demonstrate that IKZF2 regulates a HOXA9 self-renewal gene expression program and inhibits a C/EBP-driven differentiation program. Ectopic HOXA9 expression and CEBPE depletion rescued the effects of IKZF2 depletion. Thus, our study shows that IKZF2 regulates the AML LSC program and provides a rationale to therapeutically target IKZF2 in myeloid leukemia.


Asunto(s)
Diferenciación Celular , Autorrenovación de las Células , Proteínas de Unión al ADN/fisiología , Regulación Leucémica de la Expresión Génica , Leucemia Experimental/patología , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/patología , Factores de Transcripción/fisiología , Animales , Cromatina/genética , Cromatina/metabolismo , Femenino , Hematopoyesis , Leucemia Experimental/genética , Leucemia Experimental/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Madre Neoplásicas/metabolismo
8.
Cancer Cell ; 34(4): 643-658.e5, 2018 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-30270123

RESUMEN

Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression.


Asunto(s)
Proteínas de Homeodominio/genética , Leucemia Mieloide Aguda/genética , Animales , Transformación Celular Neoplásica , Elementos de Facilitación Genéticos/genética , Humanos , Metilación , Regiones Promotoras Genéticas/genética
10.
Blood ; 131(15): 1730-1742, 2018 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-29453291

RESUMEN

Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine-specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML. We performed a comparative assessment of chromatin dynamics during the treatment of mixed lineage leukemia (MLL)-AF9-driven murine leukemias and MLL-rearranged patient-derived xenografts using 2 distinct but effective differentiation-inducing targeted epigenetic therapies, the LSD1 inhibitor GSK-LSD1 and the DOT1L inhibitor EPZ4777. Intriguingly, GSK-LSD1 treatment caused global gains in chromatin accessibility, whereas treatment with EPZ4777 caused global losses in accessibility. We captured PU.1 and C/EBPα motif signatures at LSD1 inhibitor-induced dynamic sites and chromatin immunoprecipitation coupled with high-throughput sequencing revealed co-occupancy of these myeloid transcription factors at these sites. Functionally, we confirmed that diminished expression of PU.1 or genetic deletion of C/EBPα in MLL-AF9 cells generates resistance of these leukemias to LSD1 inhibition. These findings reveal that pharmacologic inhibition of LSD1 represents a unique path to overcome the differentiation block in AML for therapeutic benefit.


Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Leucemia Bifenotípica Aguda/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Animales , Proteínas Potenciadoras de Unión a CCAAT/genética , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Leucemia Bifenotípica Aguda/genética , Leucemia Bifenotípica Aguda/metabolismo , Leucemia Bifenotípica Aguda/patología , Ratones , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Proteínas Proto-Oncogénicas/genética , Elementos de Respuesta , Transactivadores/genética
11.
Cancer Cell ; 33(1): 29-43.e7, 2018 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-29249691

RESUMEN

Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor κB (NF-κB) signaling as a key pathway activated in malignant and non-malignant cells in MPN. Inhibition of BET bromodomain proteins attenuated NF-κB signaling and reduced cytokine production in vivo. Most importantly, combined JAK/BET inhibition resulted in a marked reduction in the serum levels of inflammatory cytokines, reduced disease burden, and reversed bone marrow fibrosis in vivo.


Asunto(s)
Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Janus Quinasa 2/genética , Ratones Transgénicos , Mutación/efectos de los fármacos , FN-kappa B/metabolismo , Neoplasias/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos
12.
Clin Cancer Res ; 21(10): 2348-58, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25688158

RESUMEN

PURPOSE: Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small-molecule inhibitors that target epigenetic mechanisms. EXPERIMENTAL DESIGN: A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity. Isoform-specific shRNAs were used as further validation of HDACs as relevant therapeutic targets in B-ALL. Mouse xenografts of B-cell malignancy-derived cell lines and a pediatric B-ALL were used to demonstrate pharmacologic efficacy. RESULTS: Nonselective HDAC inhibitors were cytotoxic to a panel of B-ALL cell lines as well as to xenografted human leukemia patient samples. Assessment of isoform-specific HDACi indicated that targeting HDAC1-3 with class I HDAC-specific inhibitors was sufficient to inhibit growth of B-ALL cell lines. Furthermore, shRNA-mediated knockdown of HDAC1 or HDAC2 resulted in growth inhibition in these cells. We then assessed a compound that specifically inhibits only HDAC1 and HDAC2. This compound suppressed growth and induced apoptosis in B-ALL cell lines in vitro and in vivo, whereas it was far less effective against other B-cell-derived malignancies. CONCLUSIONS: Here, we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL.


Asunto(s)
Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 2/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Animales , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Ratones SCID , Terapia Molecular Dirigida , Leucemia-Linfoma Linfoblástico de Células Precursoras B/enzimología , ARN Interferente Pequeño/genética , Ensayos Antitumor por Modelo de Xenoinjerto
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