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1.
Cell Rep ; 3(5): 1553-66, 2013 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-23623499

RESUMO

Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elongation machinery as well as the Polycomb repressive complex 1 (PRC1) component CBX8. These interactions were mutually exclusive in vitro, corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay, and this effect was neutralized by direct association with ENL. Correspondingly, CBX8-binding-defective MLL-ENL could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as a neomorphic activity that may augment Polycomb inhibition and transformation.


Assuntos
Proteína de Leucina Linfoide-Mieloide/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Fatores de Elongação da Transcrição/metabolismo , Transformação Celular Neoplásica , Dimerização , Células HEK293 , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Histona-Lisina N-Metiltransferase , Humanos , Proteína de Leucina Linfoide-Mieloide/genética , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/genética , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Fatores de Elongação da Transcrição/genética
2.
Cancer Cell ; 21(4): 517-31, 2012 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-22516260

RESUMO

Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21(CIP1) checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anticancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling toward senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development.


Assuntos
Dano ao DNA , Proteínas de Ligação a DNA/genética , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genética , Animais , Cafeína/farmacologia , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células , Transformação Celular Neoplásica , Regulação Neoplásica da Expressão Gênica , Técnicas de Introdução de Genes , Histona-Lisina N-Metiltransferase , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Transdução de Sinais
3.
Genesis ; 49(3): 142-51, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21309068

RESUMO

HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene located on chromosome 17p13.3, a region frequently hypermethylated or deleted in human neoplasias. In mouse, Hic1 is essential for embryonic development and exerts an antitumor role in adult animals. Since Hic1-deficient mice die perinatally, we generated a conditional Hic1 null allele by flanking the Hic1-coding region by loxP sites. When crossed to animals expressing Cre recombinase in a cell-specific manner, the Hic1 conditional mice will provide new insights into the function of Hic1 in developing and mature tissues. Additionally, we used gene targeting to replace sequence-encoding amino acids 186-893 of Hic1 by citrine fluorescent protein cDNA. We demonstrate that the distribution of Hic1-citrine fusion polypeptide corresponds to the expression pattern of wild-type Hic1. Consequently, Hic1-citrine "reporter" mice can be used to monitor the activity of the Hic1 locus using citrine fluorescence.


Assuntos
Alelos , Regulação da Expressão Gênica no Desenvolvimento , Genes Supressores de Tumor , Fatores de Transcrição Kruppel-Like/genética , Animais , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos/metabolismo , Feminino , Deleção de Genes , Marcação de Genes , Genes Reporter , Integrases/genética , Integrases/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Fatores de Transcrição/genética
4.
Cancer Genet Cytogenet ; 162(2): 179-82, 2005 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-16213369

RESUMO

Chromosomal translocations involving the mixed lineage leukemia gene (MLL) located at 11q23 belong to common chromosomal abnormalities in both acute lymphoblastic (ALL) and acute myeloid leukemias (AML). It has been suggested that the mechanism of MLL leukemogenesis might be a result of a gain-of-function effect of the MLL fusion gene and simultaneous loss of function of one of the MLL alleles (haploinsufficiency). One of the recurrent translocations in AML-M5 involves chromosomal locus 10p12 and results in the MLL-AF10 fusion gene. Several mechanisms leading to MLL-AF10 fusion have been reported, and they have involved rearrangement of the 11q23 region. We present a detailed structural analysis of an AML case with an extra copy of the 5' part of MLL region and its insertion into the short arm of chromosome 10, resulting in an MLL-AF10 fusion without rearrangement of the MLL alleles on both chromosomes 11. Our observation supports a role for a simple MLL gain-of-function in leukemogenesis.


Assuntos
Cromossomos Humanos Par 10 , Leucemia Monocítica Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Southern Blotting , Pré-Escolar , Duplicação Gênica , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Masculino
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