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1.
Proc Natl Acad Sci U S A ; 109(17): 6668-73, 2012 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-22493267

RESUMO

Overexpression of the brain and acute leukemia, cytoplasmic (BAALC) gene is implicated in myeloid leukemogenesis and associated with poor outcome in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients. Additionally, high BAALC expression occurs in glioblastoma, melanoma, and childhood gastrointestinal stroma tumors, suggesting an oncogenic role for BAALC. However, the mechanisms underlying the deregulated expression are unknown. We hypothesized that a common heritable genetic feature located in cis might account for overexpression of BAALC in an allele-specific manner. By sequencing the genomic region of BAALC we identified nine informative single nucleotide polymorphisms (SNPs) and tested them for a possible association with BAALC expression levels. We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis. The association of high BAALC expression with the T allele and its correlations with RUNX1 expresser status are shown in vivo in a test set (n = 253) and validation set (n = 105) of samples from cytogenetically normal AML patients from different populations. Thus, we identify a heritable genomic feature predisposing to overexpression of an oncogene, thereby possibly leading to enhanced AML leukemogenesis. Our findings further suggest that genomic variants might become useful tools in the practice of personalized medicine.


Assuntos
Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Sítios de Ligação , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas
2.
Blood ; 120(2): 249-58, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22529287

RESUMO

High BAALC expression levels are associated with poor outcome in cytogenetically normal acute myeloid leukemia (CN-AML) patients. Recently, miR-3151 was discovered in intron 1 of BAALC. To evaluate the prognostic significance of miR-3151 expression levels and to gain insight into the biologic and prognostic interplay between miR-3151 and its host, miR-3151 and BAALC expression were measured in pretreatment blood of 179 CN-AML patients. Gene-expression profiling and miRNA-expression profiling were performed using microarrays. High miR-3151 expression was associated with shorter disease-free and overall survival, whereas high BAALC expression predicted failure of complete remission and shorter overall survival. Patients exhibiting high expression of both miR-3151 and BAALC had worse outcome than patients expressing low levels of either gene or both genes. In gene-expression profiling, high miR-3151 expressers showed down-regulation of genes involved in transcriptional regulation, posttranslational modification, and cancer pathways. Two genes, FBXL20 and USP40, were validated as direct miR-3151 targets. The results of the present study show that high expression of miR-3151 is an independent prognosticator for poor outcome in CN-AML and affects different outcome end points than its host gene, BAALC. The combination of both markers identified a patient subset with the poorest outcome. This interplay between an intronic miR and its host may have important biologic implications.


Assuntos
Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Neoplásico/genética , Idoso , Idoso de 80 Anos ou mais , Análise Citogenética , Intervalo Livre de Doença , Proteínas F-Box/genética , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Ubiquitina Tiolesterase/genética
3.
Nat Genet ; 33(3): 426-9, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12590260

RESUMO

The amnionless gene, Amn, on mouse chromosome 12 encodes a type I transmembrane protein that is expressed in the extraembryonic visceral layer during gastrulation. Mice homozygous with respect to the amn mutation generated by a transgene insertion have no amnion. The embryos are severely compromised, surviving to the tenth day of gestation but seem to lack the mesodermal layers that normally produce the trunk. The Amn protein has one transmembrane domain separating a larger, N-terminal extracellular region and a smaller, C-terminal cytoplasmic region. The extracellular region harbors a cysteine-rich domain resembling those occurring in Chordin, found in Xenopus laevis embryos, and Sog, found in Drosophila melanogaster. As these cysteine-rich domains bind bone morphogenetic proteins (Bmps), it has been speculated that the cysteine-rich domain in Amn also binds Bmps. We show that homozygous mutations affecting exons 1-4 of human AMN lead to selective malabsorption of vitamin B12 (a phenotype associated with megaloblastic anemia 1, MGA1; OMIM 261100; refs. 5,6) in otherwise normal individuals, suggesting that the 5' end of AMN is dispensable for embryonic development but necessary for absorption of vitamin B12. When the 5' end of AMN is truncated by mutations, translation is initiated from alternative downstream start codons.


Assuntos
Anemia Megaloblástica/genética , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Mutação , Âmnio/anormalidades , Animais , Sequência de Bases , DNA/genética , Análise Mutacional de DNA , Feminino , Gástrula , Genes Recessivos , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem
4.
Gastroenterology ; 141(6): 2039-46, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21893118

RESUMO

BACKGROUND & AIMS: Expression of the netrin-1 dependence receptor UNC5C is reduced in many colorectal tumors; mice with the UNC5C mutations have increased progression of intestinal tumors. We investigated whether specific variants in UNC5C increase risk of colorectal cancer (CRC). METHODS: We analyzed the sequence of UNC5C in blood samples from 1801 patients with CRC and 4152 controls from 3 cohorts (France, United States, and Finland). Almost all cases from France and the United States had familial CRC; of the Finnish cases, 92 of 984 were familial. We analyzed whether CRC segregates with the UNC5C variant A628K in 3 families with histories of CRC. We also performed haplotype analysis to determine the origin of this variant. RESULTS: Of 817 patients with familial CRC, 14 had 1 of 4 different, unreported missense variants in UNC5C. The variants p.Asp353Asn (encodes D353N), p.Arg603Cys (encodes R603C), and p.Gln630Glu (encodes Q630E) did not occur significantly more often in cases than controls. The variant p.Ala628Lys (A628K) was detected in 3 families in the French cohort (odds ratio, 8.8; Wald's 95% confidence interval, 1.47-52.93; P = .03) and in 2 families in the US cohort (odds ratio, 1.9; P = .6) but was not detected in the Finnish cohort; UNC5C A628K segregated with CRC in families. Three families with A628K had a 109-kilobase identical haplotype that spanned most of UNC5C, indicating recent origin of this variant in white subjects (14 generations; 95% confidence interval, 6-36 generations). Transfection of HEK293T cells with UNC5C-A628K significantly reduced apoptosis compared with wild-type UNC5C, measured in an assay of active caspase-3. CONCLUSIONS: Inherited mutations in UNC5C prevent apoptosis and increase risk of CRC.


Assuntos
Polipose Adenomatosa do Colo/genética , Apoptose/genética , Mutação de Sentido Incorreto/genética , Receptores de Superfície Celular/genética , Polipose Adenomatosa do Colo/sangue , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Predisposição Genética para Doença , Haplótipos/genética , Humanos , Immunoblotting , Imuno-Histoquímica , Receptores de Netrina , Linhagem , Reação em Cadeia da Polimerase , Receptores de Superfície Celular/sangue , Fatores de Risco
5.
J Pediatr Hematol Oncol ; 34(2): 140-2, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22082743

RESUMO

We report a rare case of juvenile cobalamin deficiency who presented at the age of 17 years. He was underweight and had skin changes, normocytic anemia, and autonomic dysfunction, which led to adynamic ileus and acute postrenal failure. The expected macrocytosis was masked by an underlying alpha-thalassemia trait. The patient had an excellent response to parenteral cobalamin treatment.


Assuntos
Doenças do Sistema Nervoso Autônomo/etiologia , Exantema/etiologia , Deficiência de Vitamina B 12/complicações , Vitamina B 12/sangue , Adolescente , Criptorquidismo/complicações , Gastrosquise/complicações , Humanos , Hidronefrose/complicações , Hidronefrose/congênito , Masculino , Rim Displásico Multicístico/complicações , Obstrução Ureteral/complicações , Obstrução Ureteral/congênito , Deficiência de Vitamina B 12/fisiopatologia
6.
Pediatr Res ; 70(3): 222-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21623254

RESUMO

Fifty years have passed since the description of juvenile selective malabsorption of cobalamin (Cbl). Quality of life improvements have dramatically reduced the incidence of parasite-induced or nutritional Cbl deficiency. Consequently, inherited defects have become a leading cause of Cbl deficiency in children, which is not always expressed as anemia. Unfortunately, the gold standard for clinical diagnosis, the Schilling test, has increasingly become unavailable, and replacement tests are only in their infancy. Genetic testing is complicated by genetic heterogeneity and differential diagnosis. This review documents the history, research, and advances in genetics that have elucidated the causes of juvenile Cbl malabsorption. Genetic research has unearthed many cases in the past decade, mostly in Europe and North America, often among immigrants from the Middle East or North Africa. Lack of suitable clinical testing potentially leaves many patients inadequately diagnosed. The consequences of suboptimal Cbl levels for neurological development are well documented. By raising awareness, we wish to push for fast track development of better clinical tools and suitable genetic testing. Clinical awareness must include attention to ethnicity, a sensitive topic but effective for fast diagnosis. The treatment with monthly parenteral Cbl for life offers a simple and cost-effective solution once proper diagnosis is made.


Assuntos
Testes Genéticos , Síndromes de Malabsorção/complicações , Síndromes de Malabsorção/genética , Deficiência de Vitamina B 12/etiologia , Deficiência de Vitamina B 12/genética , Vitamina B 12/metabolismo , Análise Mutacional de DNA , Humanos , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/terapia , Teste de Schilling , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/terapia
7.
EMBO Rep ; 10(11): 1272-8, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19779484

RESUMO

Nuclear factor (NF)-kappaB is a positive regulator of tumour development and progression, but how it functions in normal cells leading to oncogenesis is not clear. As cellular senescence has proven to be an intrinsic tumour suppressor mechanism that cells must overcome to establish deregulated growth, we used primary fibroblasts to follow NF-kappaB function in cells transitioning from senescence to subsequent immortalization. Our findings show that RelA/p65(-/-) murine fibroblasts immortalize at considerably faster rates than RelA/p65(+/+) cells. The ability of RelA/p65(-/-) fibroblasts to escape senescence earlier is due to their genomic instability, characterized by high frequencies of DNA mutations, gene deletions and gross chromosomal translocations. This increase in genomic instability is closely related to a compromised DNA repair that occurs in both murine RelA/p65(-/-) fibroblasts and tissues. Significantly, these results can also be duplicated in human fibroblasts lacking NF-kappaB. Altogether, our findings present a fresh perspective on the role of NF-kappaB as a tumour suppressor, which acts in pre-neoplastic cells to maintain cellular senescence by promoting DNA repair and genomic stability.


Assuntos
Senescência Celular , Reparo do DNA , Instabilidade Genômica , Fator de Transcrição RelA/metabolismo , Células 3T3 , Animais , Linhagem Celular , DNA/genética , Fibroblastos/metabolismo , Deleção de Genes , Peróxido de Hidrogênio/química , Camundongos , Mutação , NF-kappa B/metabolismo , Translocação Genética
8.
Carcinogenesis ; 31(10): 1800-4, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20705955

RESUMO

The genetic component of colorectal cancer (CRC) predisposition has been only partially explained. We recently suggested that a subtle decrease in the expression of one allele of the TGFBR1 gene was a heritable quantitative trait predisposing to CRC. Here, we refined the measurements of allele-specific expression (ASE) of TGFBR1 in a population-based series of CRC patients and controls. Five single-nucleotide polymorphisms (SNPs) in the 3'-untranslated region of the gene were genotyped and used for ASE determination by pyrosequencing. After eliminating non-informative samples and samples with RNA of insufficient quality 109 cases and 125 controls were studied. Allelic ratios ranged between 0.74 and 1.69 without evidence of bimodality or cutoff points for 'ASE' versus 'non-ASE'. Treating ASE as a continuous variable, cases had non-significantly different values than controls (P = 0.081 when comparing means by permutation test). However, cases had significantly higher ASE values when comparing medians by permutation test (P = 0.0027) and when using Wilcoxon test (P = 0.0094). We conclude that with the present-day technology, ASE differences between individuals and between cases and controls are too subtle to be used to assess CRC risk. More advanced technology is expected to resolve this issue as well as the low informativity caused by the limited heterozygosity of transcribed SNPs.


Assuntos
Neoplasias do Colo/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Característica Quantitativa Herdável , Receptor do Fator de Crescimento Transformador beta Tipo I
10.
Br J Haematol ; 139(5): 744-52, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17961188

RESUMO

Molecular profiling may lead to a better understanding of a disease. This knowledge is especially important in malignancies, where multiple alterations are required during the progression from premalignant to malignant stages. Such information can be useful for the development of novel biomarkers that allow the prediction of a clinical course, response to treatment or early detection. Molecular data is also utilized to develop targeted therapies. Moreover, gene defects identified in profiling studies will help to understand the molecular pathways disrupted in the disease. This review provides an overview of molecular profiling approaches in chronic lymphocytic leukaemia (CLL). We will describe our current understanding of genetic alterations in CLL, the use of familial CLL for the identification of predisposing mutations, and the search for epigenetic alterations in CLL.


Assuntos
Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Proteínas Quinases Associadas com Morte Celular , Epigênese Genética , Perfilação da Expressão Gênica/métodos , Inativação Gênica , Genômica , Humanos
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