RESUMO
In the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), NF-κB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IκB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-κB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B-cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/enzimologia , Proteínas Nucleares/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Adenina/análogos & derivados , Animais , Azepinas/farmacologia , Azepinas/toxicidade , Proteínas de Ciclo Celular , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular , Sinergismo Farmacológico , Humanos , Quinase I-kappa B/química , Quinase I-kappa B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos SCID , Proteínas Nucleares/metabolismo , Piperidinas , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Triazóis/farmacologia , Triazóis/toxicidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Impaired apoptosis is a cancer hallmark, and some types of lymphomas and other cancers harbor mutations that directly affect key cell death regulators, such as Bcl-2 family members. However, because the majority of tumors seem to lack such mutations, we are examining the hypothesis that tumorigenesis can be sustained at least initially by the normal expression of specific endogenous pro-survival Bcl-2 family members. We previously demonstrated that the lymphomagenesis in Εµ-myc transgenic mice, which constitutively overexpress the c-Myc oncoprotein in B-lymphoid cells and develop pre-B and B-cell lymphomas, does not require endogenous Bcl-2. In striking contrast, we report here that loss in these mice of its close relative Bcl-x(L) attenuated the pre-neoplastic expansion of pro-B and pre-B cells otherwise driven by c-Myc overexpression, sensitized these cells to apoptosis and ablated lymphoma formation. Remarkably, even loss of a single bcl-x allele delayed the lymphomagenesis. These findings identify Bcl-x(L) as a prerequisite for the emergence of c-Myc-driven pre-B/B lymphoma and suggest that BH3 mimetic drugs may provide a prophylactic strategy for c-Myc-driven tumors.
Assuntos
Linfócitos B/metabolismo , Transformação Celular Neoplásica/metabolismo , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Regulação para Cima , Proteína bcl-X/metabolismo , Animais , Apoptose , Linfócitos B/citologia , Células Cultivadas , Cruzamentos Genéticos , Feminino , Heterozigoto , Linfoma de Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos B/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Análise de Sobrevida , Proteína bcl-X/genéticaRESUMO
Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.