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1.
Nat Med ; 24(8): 1157-1166, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30038221

RESUMO

Cellular transformation is accompanied by extensive rewiring of many biological processes leading to augmented levels of distinct types of cellular stress, including proteotoxic stress. Cancer cells critically depend on stress-relief pathways for their survival. However, the mechanisms underlying the transcriptional initiation and maintenance of the oncogenic stress response remain elusive. Here, we show that the expression of heat shock transcription factor 1 (HSF1) and the downstream mediators of the heat shock response is transcriptionally upregulated in T cell acute lymphoblastic leukemia (T-ALL). Hsf1 ablation suppresses the growth of human T-ALL and eradicates leukemia in mouse models of T-ALL, while sparing normal hematopoiesis. HSF1 drives a compact transcriptional program and among the direct HSF1 targets, specific chaperones and co-chaperones mediate its critical role in T-ALL. Notably, we demonstrate that the central T-ALL oncogene NOTCH1 hijacks the cellular stress response machinery by inducing the expression of HSF1 and its downstream effectors. The NOTCH1 signaling status controls the levels of chaperone/co-chaperone complexes and predicts the response of T-ALL patient samples to HSP90 inhibition. Our data demonstrate an integral crosstalk between mediators of oncogene and non-oncogene addiction and reveal critical nodes of the heat shock response pathway that can be targeted therapeutically.

2.
BMC Genomics ; 18(1): 434, 2017 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-28583068

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as a class of factors that are important for regulating development and cancer. Computational prediction of lncRNAs from ultra-deep RNA sequencing has been successful in identifying candidate lncRNAs. However, the complexity of handling and integrating different types of genomics data poses significant challenges to experimental laboratories that lack extensive genomics expertise. RESULT: To address this issue, we have developed lncRNA-screen, a comprehensive pipeline for computationally screening putative lncRNA transcripts over large multimodal datasets. The main objective of this work is to facilitate the computational discovery of lncRNA candidates to be further examined by functional experiments. lncRNA-screen provides a fully automated easy-to-run pipeline which performs data download, RNA-seq alignment, assembly, quality assessment, transcript filtration, novel lncRNA identification, coding potential estimation, expression level quantification, histone mark enrichment profile integration, differential expression analysis, annotation with other type of segmented data (CNVs, SNPs, Hi-C, etc.) and visualization. Importantly, lncRNA-screen generates an interactive report summarizing all interesting lncRNA features including genome browser snapshots and lncRNA-mRNA interactions based on Hi-C data. CONCLUSION: lncRNA-screen provides a comprehensive solution for lncRNA discovery and an intuitive interactive report for identifying promising lncRNA candidates. lncRNA-screen is available as open-source software on GitHub.


Assuntos
Bases de Dados Genéticas , Genômica/métodos , RNA Longo não Codificante/genética , Interface Usuário-Computador , Mineração de Dados , Epigenômica , Perfilação da Expressão Gênica , Histonas/metabolismo , Alinhamento de Sequência , Software
3.
Nat Cell Biol ; 18(11): 1127-1138, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27749823

RESUMO

Pluripotent embryonic stem cells (ESCs) self-renew or differentiate into all tissues of the developing embryo and cell-specification factors are necessary to balance gene expression. Here we delineate the function of the PHD-finger protein 5a (Phf5a) in ESC self-renewal and ascribe its role in regulating pluripotency, cellular reprogramming and myoblast specification. We demonstrate that Phf5a is essential for maintaining pluripotency, since depleted ESCs exhibit hallmarks of differentiation. Mechanistically, we attribute Phf5a function to the stabilization of the Paf1 transcriptional complex and control of RNA polymerase II elongation on pluripotency loci. Apart from an ESC-specific factor, we demonstrate that Phf5a controls differentiation of adult myoblasts. Our findings suggest a potent mode of regulation by Phf5a in stem cells, which directs their transcriptional programme, ultimately regulating maintenance of pluripotency and cellular reprogramming.


Assuntos
Proteínas de Transporte/genética , Diferenciação Celular/genética , Reprogramação Celular/genética , Células-Tronco Embrionárias Murinas/citologia , Mioblastos/citologia , Células-Tronco Pluripotentes/citologia , Transcrição Genética , Envelhecimento , Animais , Linhagem Celular , Proliferação de Células/genética , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Camundongos Endogâmicos C57BL
4.
Cell Rep ; 15(10): 2159-2169, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27239026

RESUMO

V(D)J recombination relies on the presence of proximal enhancers that activate the antigen receptor (AgR) loci in a lineage- and stage-specific manner. Unexpectedly, we find that both active and inactive AgR enhancers cooperate to disseminate their effects in a localized and long-range manner. Here, we demonstrate the importance of short-range contacts between active enhancers that constitute an Igk super-enhancer in B cells. Deletion of one element reduces the interaction frequency between other enhancers in the hub, which compromises the transcriptional output of each component. Furthermore, we establish that, in T cells, long-range contact and cooperation between the inactive Igk enhancer MiEκ and the active Tcrb enhancer Eß alters enrichment of CBFß binding in a manner that impacts Tcrb recombination. These findings underline the complexities of enhancer regulation and point to a role for localized and long-range enhancer-sharing between active and inactive elements in lineage- and stage-specific control.


Assuntos
Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Animais , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Camundongos Endogâmicos C57BL , Ligação Proteica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/imunologia
6.
Cancer Cell ; 27(6): 755-68, 2015 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-26058075

RESUMO

The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL.


Assuntos
Quimiocina CXCL12/antagonistas & inibidores , Quimiocina CXCL12/biossíntese , Endotélio Vascular/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Piridinas/farmacologia , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Quimiocina CXCL12/genética , Endotélio Vascular/patologia , Feminino , Deleção de Genes , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Células Estromais/metabolismo , Células Estromais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nat Immunol ; 16(6): 653-62, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25867473

RESUMO

The methylcytosine dioxygenase TET1 ('ten-eleven translocation 1') is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy.


Assuntos
Linfócitos B/fisiologia , Citosina/análogos & derivados , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/fisiologia , Linfoma de Células B/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , 5-Metilcitosina/análogos & derivados , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Instabilidade Cromossômica , Citosina/metabolismo , Metilação de DNA , Reparo do DNA , Proteínas de Ligação a DNA/genética , Epigênese Genética , Exoma/genética , Perfilação da Expressão Gênica , Humanos , Camundongos , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética
8.
Cancer Cell ; 27(3): 321-3, 2015 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-25759017

RESUMO

Pre B-ALL is an aggressive cancer of the blood for which treatment of patients with relapsed and refractory disease remains a challenge. In this issue of Cancer Cell, Geng and colleagues surveyed the activation status of the pre-B cell receptor and comprehensively investigated downstream signaling mechanisms currently targetable with small molecule inhibitors.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Regulação Neoplásica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-bcl-6
9.
Nat Cell Biol ; 17(3): 322-332, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25720964

RESUMO

​Heat-shock factor 1 (​HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate ​HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase ​FBXW7α interacts with ​HSF1 through a conserved motif phosphorylated by ​GSK3ß and ​ERK1. ​FBXW7α ubiquitylates ​HSF1 and loss of ​FBXW7α results in impaired degradation of nuclear ​HSF1 and defective heat-shock response attenuation. ​FBXW7α is either mutated or transcriptionally downregulated in melanoma and ​HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. ​FBXW7α deficiency and subsequent ​HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the ​HSF1 transcriptional program both in the presence of exogenous stress and in cancer.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas F-Box/genética , Quinase 3 da Glicogênio Sintase/genética , Melanoma/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Processamento de Proteína Pós-Traducional , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Sequência de Aminoácidos , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Proteínas F-Box/metabolismo , Proteína 7 com Repetições F-Box-WD , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células HEK293 , Fatores de Transcrição de Choque Térmico , Humanos , Luciferases/genética , Luciferases/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Nus , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Dados de Sequência Molecular , Metástase Neoplásica , Transplante de Neoplasias , Alinhamento de Sequência , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
10.
Cell ; 158(3): 593-606, 2014 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-25083870

RESUMO

Notch signaling is a key developmental pathway that is subject to frequent genetic and epigenetic perturbations in many different human tumors. Here we investigate whether long noncoding RNA (lncRNA) genes, in addition to mRNAs, are key downstream targets of oncogenic Notch1 in human T cell acute lymphoblastic leukemia (T-ALL). By integrating transcriptome profiles with chromatin state maps, we have uncovered many previously unreported T-ALL-specific lncRNA genes, a fraction of which are directly controlled by the Notch1/Rpbjκ activator complex. Finally we have shown that one specific Notch-regulated lncRNA, LUNAR1, is required for efficient T-ALL growth in vitro and in vivo due to its ability to enhance IGF1R mRNA expression and sustain IGF1 signaling. These results confirm that lncRNAs are important downstream targets of the Notch signaling pathway, and additionally they are key regulators of the oncogenic state in T-ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , RNA Longo não Codificante/análise , Receptor Notch1/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , RNA Longo não Codificante/genética , Transdução de Sinais , Timo/patologia
11.
Nature ; 514(7523): 513-7, 2014 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-25132549

RESUMO

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.


Assuntos
Histona Desmetilases/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Animais , Benzazepinas/farmacologia , Epigênese Genética/efeitos dos fármacos , Histona Desmetilases/genética , Histonas/química , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Lisina/metabolismo , Metilação/efeitos dos fármacos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Pirimidinas/farmacologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
12.
J Exp Med ; 210(12): 2641-59, 2013 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-24218140

RESUMO

Somatic Addition of Sex Combs Like 1 (ASXL1) mutations occur in 10-30% of patients with myeloid malignancies, most commonly in myelodysplastic syndromes (MDSs), and are associated with adverse outcome. Germline ASXL1 mutations occur in patients with Bohring-Opitz syndrome. Here, we show that constitutive loss of Asxl1 results in developmental abnormalities, including anophthalmia, microcephaly, cleft palates, and mandibular malformations. In contrast, hematopoietic-specific deletion of Asxl1 results in progressive, multilineage cytopenias and dysplasia in the context of increased numbers of hematopoietic stem/progenitor cells, characteristic features of human MDS. Serial transplantation of Asxl1-null hematopoietic cells results in a lethal myeloid disorder at a shorter latency than primary Asxl1 knockout (KO) mice. Asxl1 deletion reduces hematopoietic stem cell self-renewal, which is restored by concomitant deletion of Tet2, a gene commonly co-mutated with ASXL1 in MDS patients. Moreover, compound Asxl1/Tet2 deletion results in an MDS phenotype with hastened death compared with single-gene KO mice. Asxl1 loss results in a global reduction of H3K27 trimethylation and dysregulated expression of known regulators of hematopoiesis. RNA-Seq/ChIP-Seq analyses of Asxl1 in hematopoietic cells identify a subset of differentially expressed genes as direct targets of Asxl1. These findings underscore the importance of Asxl1 in Polycomb group function, development, and hematopoiesis.


Assuntos
Anormalidades Múltiplas/etiologia , Síndromes Mielodisplásicas/etiologia , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Anormalidades Múltiplas/genética , Animais , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Epigênese Genética , Feminino , Deleção de Genes , Mutação em Linhagem Germinativa , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Fenótipo , Gravidez , Ligação Proteica , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/metabolismo
13.
Nat Genet ; 45(8): 846-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23892662

RESUMO

Recent studies have identified recurrent mutations in SETBP1, the gene that encodes SET-binding protein 1, in several types of myeloid malignancies, including chronic myeloid and acute myeloid leukemias. The identified mutations frequently target the SKI-homologous domain, although the exact pathogenic mechanisms remain unknown.


Assuntos
Proteínas de Transporte/genética , Exoma , Janus Quinase 3/genética , Leucemia Mieloide/genética , Leucemia Mielomonocítica Juvenil/genética , Mutação , Transtornos Mieloproliferativos/genética , Proteínas Nucleares/genética , Animais , Feminino , Humanos , Masculino
14.
Cell ; 153(7): 1552-66, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23791182

RESUMO

Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Modelos Animais de Doenças , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Receptor Notch1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
15.
Adv Immunol ; 117: 1-38, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23611284

RESUMO

Over the past decade, it has become clear that both genetics and epigenetics play pivotal roles in cancer onset and progression. The importance of epigenetic regulation in proper maintenance of cellular state is highlighted by the frequent mutation of chromatin modulating factors across cancer subtypes. Identification of these mutations has created an interest in designing drugs that target enzymes involved in DNA methylation and posttranslational modification of histones. In this review, we discuss recurrent genetic alterations to epigenetic modulators in both myeloid and lymphoid leukemias. Furthermore, we review how these perturbations contribute to leukemogenesis and impact disease outcome and treatment efficacy. Finally, we discuss how the recent advances in our understanding of chromatin biology may impact treatment of leukemia.


Assuntos
Epigênese Genética/genética , Epigênese Genética/imunologia , Leucemia/genética , Leucemia/imunologia , Metilação de DNA/genética , Metilação de DNA/imunologia , Progressão da Doença , Hematopoese/genética , Hematopoese/imunologia , Histona-Lisina N-Metiltransferase , Humanos , Leucemia/patologia , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas do Grupo Polycomb/genética
16.
Cancer Cell ; 22(4): 452-65, 2012 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-23079656

RESUMO

D-type cyclins form complexes with cyclin-dependent kinases (CDK4/6) and promote cell cycle progression. Although cyclin D functions appear largely tissue specific, we demonstrate that cyclin D3 has unique functions in lymphocyte development and cannot be replaced by cyclin D2, which is also expressed during blood differentiation. We show that only combined deletion of p27(Kip1) and retinoblastoma tumor suppressor (Rb) is sufficient to rescue the development of Ccnd3(-/-) thymocytes. Furthermore, we show that a small molecule targeting the kinase function of cyclin D3:CDK4/6 inhibits both cell cycle entry in human T cell acute lymphoblastic leukemia (T-ALL) and disease progression in animal models of T-ALL. These studies identify unique functions for cyclin D3:CDK4/6 complexes and suggest potential therapeutic protocols for this devastating blood tumor.


Assuntos
Ciclina D3/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Animais , Ciclina D2/fisiologia , Ciclina D3/fisiologia , Quinase 4 Dependente de Ciclina/fisiologia , Quinase 6 Dependente de Ciclina/fisiologia , Inibidor de Quinase Dependente de Ciclina p27/fisiologia , Humanos , Linfócitos/fisiologia , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Receptor Notch1/fisiologia , Proteína do Retinoblastoma/fisiologia
17.
Mol Cell ; 47(6): 873-85, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-22864115

RESUMO

Class switch recombination (CSR) has the potential to generate genomic instability in B cells as activation-induced cytidine deaminase (AID), which mediates this process, is known to target many sites outside Igh. Nonetheless we do not fully understand what factors influence AID targeting genome-wide. Given that errors in CSR can lead to dangerous, oncogenic chromosomal translocations it is important to identify the elements that determine which genes are at risk of being "hit" and could be involved in aberrant rearrangements. Here we have investigated the influence of nuclear organization in determining "off-target" activity and the choice of fusion partners. Our studies indicate that the vast majority of known AID-mediated Igh translocation partners are found in chromosomal domains that contact this locus during class switching. Further, these interaction domains can be used to identify other genes that are hit by AID.


Assuntos
Linfócitos B/citologia , Citidina Desaminase/metabolismo , Genes de Cadeia Pesada de Imunoglobulina , Switching de Imunoglobulina , Translocação Genética , Animais , Linfócitos B/metabolismo , Citidina Desaminase/genética , Instabilidade Genômica , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Hipermutação Somática de Imunoglobulina
18.
Nat Med ; 18(2): 298-301, 2012 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-22237151

RESUMO

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3) by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Repressoras/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica/genética , Inativação Gênica/fisiologia , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Complexo Repressor Polycomb 2 , Proteínas do Grupo Polycomb , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Nature ; 473(7346): 230-3, 2011 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-21562564

RESUMO

Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types. Its activity is controlled by the multi-subunit γ-secretase (γSE) complex. Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations. Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signalling during early haematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/patologia , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Células Cultivadas , Perfilação da Expressão Gênica , Inativação Gênica , Células Progenitoras de Granulócitos e Macrófagos/citologia , Células Progenitoras de Granulócitos e Macrófagos/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Receptores Notch/deficiência , Fatores de Transcrição HES-1 , Células Tumorais Cultivadas
20.
Cancer Cell ; 18(3): 268-81, 2010 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-20832754

RESUMO

It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Homeodomínio/metabolismo , Leucemia de Células T/metabolismo , NF-kappa B/metabolismo , Receptores Notch/metabolismo , Proteínas Supressoras de Tumor/antagonistas & inibidores , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Enzima Desubiquitinante CYLD , Genes Supressores de Tumor , Proteínas de Homeodomínio/genética , Humanos , Leucemia de Células T/genética , Leucemia de Células T/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , Receptores Notch/genética , Transdução de Sinais , Fatores de Transcrição HES-1 , Fator de Transcrição RelA/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
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