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1.
Genome Res ; 27(6): 922-933, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28341771

RESUMEN

The spatial arrangement of chromatin is linked to the regulation of nuclear processes. One striking aspect of nuclear organization is the spatial segregation of heterochromatic and euchromatic domains. The mechanisms of this chromatin segregation are still poorly understood. In this work, we investigated the link between the primary genomic sequence and chromatin domains. We analyzed the spatial intranuclear arrangement of a human artificial chromosome (HAC) in a xenospecific mouse background in comparison to an orthologous region of native mouse chromosome. The two orthologous regions include segments that can be assigned to three major chromatin classes according to their gene abundance and repeat repertoire: (1) gene-rich and SINE-rich euchromatin; (2) gene-poor and LINE/LTR-rich heterochromatin; and (3) gene-depleted and satellite DNA-containing constitutive heterochromatin. We show, using fluorescence in situ hybridization (FISH) and 4C-seq technologies, that chromatin segments ranging from 0.6 to 3 Mb cluster with segments of the same chromatin class. As a consequence, the chromatin segments acquire corresponding positions in the nucleus irrespective of their chromosomal context, thereby strongly suggesting that this is their autonomous property. Interactions with the nuclear lamina, although largely retained in the HAC, reveal less autonomy. Taken together, our results suggest that building of a functional nucleus is largely a self-organizing process based on mutual recognition of chromosome segments belonging to the major chromatin classes.


Asunto(s)
Núcleo Celular/genética , Cromosomas Artificiales Humanos/metabolismo , Eucromatina/metabolismo , Fibroblastos/metabolismo , Heterocromatina/metabolismo , Retina/metabolismo , Animales , Línea Celular Transformada , Núcleo Celular/metabolismo , Núcleo Celular/ultraestructura , Cromosomas Artificiales Humanos/ultraestructura , Eucromatina/clasificación , Eucromatina/ultraestructura , Fibroblastos/ultraestructura , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Heterocromatina/clasificación , Heterocromatina/ultraestructura , Humanos , Hibridación Fluorescente in Situ , Ratones , Cultivo Primario de Células , Retina/ultraestructura
2.
Nat Immunol ; 9(3): 263-71, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18223652

RESUMEN

The paracaspase MALT1 mediates T cell antigen receptor-induced signaling to the transcription factor NF-kappaB and is indispensable for T cell activation and proliferation. Enhanced expression of MALT1 or aberrant expression of a fusion protein of the apoptosis inhibitor API2 and MALT1 has been linked to mucosa-associated lymphoid tissue lymphoma. Despite the presence of a caspase-like domain, MALT1 proteolytic activity has not yet been demonstrated. Here we show that T cell antigen receptor stimulation induced recruitment of the NF-kappaB inhibitor A20 into a complex of MALT1 and the adaptor protein Bcl-10, leading to MALT1-mediated processing of A20. API2-MALT1 expression likewise resulted in cleavage of A20. MALT1 cleaved human A20 after arginine 439 and impaired its NF-kappaB-inhibitory function. Our studies identify A20 as a substrate of MALT1 and emphasize the importance of MALT1 proteolytic activity in the 'fine tuning' of T cell antigen receptor signaling.


Asunto(s)
Caspasas/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , FN-kappa B/antagonistas & inhibidores , Proteínas de Neoplasias/fisiología , Proteínas Nucleares/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Caspasas/genética , Línea Celular , Proteínas de Unión al ADN , Humanos , Immunoblotting , Células Jurkat , Activación de Linfocitos/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas de Neoplasias/genética , Péptido Hidrolasas/fisiología , Transducción de Señal/inmunología , Transfección , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa
3.
Eur J Immunol ; 48(10): 1728-1738, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30025160

RESUMEN

Mucosa-associated lymphoid tissue 1 (Malt1) regulates immune cell function by mediating the activation of nuclear factor κB (NF-κB) signaling through both its adaptor and proteolytic function. Malt1 is also a target of its own protease activity and this self-cleavage further contributes to NF-κB activity. Until now, the functional distinction between Malt1 self-cleavage and its general protease function in regulating NF-κB signaling and immune activation remained unclear. Here we demonstrate, using a new mouse model, the importance of Malt1 self-cleavage in regulating expression of NF-κB target genes and subsequent T cell activation. Significantly, we further establish that Treg homeostasis is critically linked to Malt1 function via a Treg intrinsic and extrinsic mechanism. TCR-mediated Malt1 proteolytic activity and self-cleavage was found to drive Il2 expression in conventional CD4+ T cells, thereby regulating Il2 availability for Treg homeostasis. Remarkably, the loss of Malt1-mediated self-cleavage alone was sufficient to cause a significant Treg deficit resulting in increased anti-tumor immune reactivity without associated autoimmunity complications. These results establish for the first time that inhibition of MALT1 proteolytic activity could be a viable therapeutic strategy to augment anti-tumor immunity.


Asunto(s)
Activación de Linfocitos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Animales , Regulación de la Expresión Génica , Homeostasis , Interleucina-2/inmunología , Ratones , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , FN-kappa B/genética , Proteínas de Neoplasias/inmunología , Proteolisis , Transducción de Señal/inmunología
4.
Hum Mutat ; 37(8): 804-11, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27159028

RESUMEN

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole-exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.


Asunto(s)
Variación Genética , Discapacidad Intelectual/genética , Análisis de Secuencia de ADN/métodos , Inactivación del Cromosoma X , Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , ARN Helicasas DEAD-box/genética , Exoma , Femenino , Humanos , Proteínas de la Membrana , Proteína 2 de Unión a Metil-CpG/genética , Proteínas Nucleares/genética
5.
Mol Cell ; 31(1): 134-42, 2008 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-18614052

RESUMEN

Genetic alterations causing constitutive tyrosine kinase activation are observed in a broad spectrum of cancers. Thus far, these mutant kinases have been localized to the plasma membrane or cytoplasm, where they engage proliferation and survival pathways. We report that the NUP214-ABL1 fusion is unique among these because of its requisite localization to the nuclear pore complex for its transforming potential. We show that NUP214-ABL1 displays attenuated transforming capacity as compared to BCR-ABL1 and that NUP214-ABL1 preferentially transforms T cells, which is in agreement with its unique occurrence in T cell acute lymphoblastic leukemia. Furthermore, NUP214-ABL1 differs from BCR-ABL1 in subcellular localization, initiation of kinase activity, and signaling and lacks phosphorylation on its activation loop. In addition to delineating an unusual mechanism for kinase activation, this study provides new insights into the spectrum of chromosomal translocations involving nucleoporins by indicating that the nuclear pore context itself may play a central role in transformation.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Poro Nuclear/enzimología , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Animales , Línea Celular , Activación Enzimática , Humanos , Ratones , Proteínas de Complejo Poro Nuclear/metabolismo
6.
Nat Genet ; 39(9): 1120-6, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17704776

RESUMEN

We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease.


Asunto(s)
Mutación de Línea Germinal , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Adulto , Anciano , Análisis de Varianza , Línea Celular , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Immunoblotting , Lactante , Péptidos y Proteínas de Señalización Intracelular/fisiología , Masculino , Proteínas de la Membrana/fisiología , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neurofibromatosis 1/metabolismo , Linaje , Fenotipo , Transducción de Señal/genética , Transducción de Señal/fisiología , Proteínas ras/metabolismo
7.
Nat Genet ; 39(5): 593-5, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17435759

RESUMEN

We identified a duplication of the MYB oncogene in 8.4% of individuals with T cell acute lymphoblastic leukemia (T-ALL) and in five T-ALL cell lines. The duplication is associated with a threefold increase in MYB expression, and knockdown of MYB expression initiates T cell differentiation. Our results identify duplication of MYB as an oncogenic event and suggest that MYB could be a therapeutic target in human T-ALL.


Asunto(s)
Diferenciación Celular/genética , Duplicación de Gen , Genes myb/genética , Leucemia-Linfoma de Células T del Adulto/genética , Linfocitos T/patología , Diferenciación Celular/inmunología , Línea Celular Tumoral , Cromosomas Artificiales/genética , Citometría de Flujo , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica/genética , Pruebas Genéticas , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Mutación/genética , Hibridación de Ácido Nucleico/genética , ARN Interferente Pequeño/genética , Estadísticas no Paramétricas
8.
Am J Hum Genet ; 91(2): 252-64, 2012 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-22840365

RESUMEN

We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3' untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.


Asunto(s)
Cromosomas Humanos X/genética , Variaciones en el Número de Copia de ADN/genética , Reordenamiento Génico/genética , Discapacidad Intelectual/genética , Ubiquitina-Proteína Ligasas/genética , Mapeo Cromosómico , Cromosomas Artificiales Bacterianos/genética , Hibridación Genómica Comparativa , Biología Computacional , Replicación del ADN/genética , Duplicación de Gen/genética , Humanos , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple/genética , Recombinación Genética/genética , Proteínas Supresoras de Tumor
9.
Nat Genet ; 38(12): 1419-23, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17115058

RESUMEN

Several large-scale studies of human genetic variation have provided insights into processes such as recombination that have shaped human diversity. However, regions such as low-copy repeats (LCRs) have proven difficult to characterize, hindering efforts to understand the processes operating in these regions. We present a detailed study of genetic variation and underlying recombination processes in two copies of an LCR (NF1REPa and NF1REPc) on chromosome 17 involved in the generation of NF1 microdeletions and in a third copy (REP19) on chromosome 19 from which the others originated over 6.7 million years ago. We find evidence for shared hotspots of recombination among the LCRs. REP19 seems to contain hotspots in the same place as the nonallelic recombination hotspots in NF1REPa and NF1REPc. This apparent conservation of patterns of recombination hotspots in moderately diverged paralogous regions contrasts with recent evidence that these patterns are not conserved in less-diverged orthologous regions of chimpanzees.


Asunto(s)
Genes de Neurofibromatosis 1 , Eliminación de Secuencia , Animales , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 19/genética , Secuencia Conservada , Evolución Molecular , Haplotipos , Humanos , Pan troglodytes/genética , Polimorfismo de Nucleótido Simple , Recombinación Genética , Secuencias Repetitivas de Ácidos Nucleicos
10.
Hum Genet ; 133(11): 1359-67, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25037250

RESUMEN

Xq28 microduplications of MECP2 are a prominent cause of a severe syndromic form of intellectual disability (ID) in males. Females are usually unaffected through near to complete X-inactivation of the aberrant X chromosome (skewing). In rare cases, affected females have been described due to random X-inactivation. Here, we report on two female patients carrying de novo MECP2 microduplications on their fully active X chromosomes. Both patients present with ID and additional clinical features. Mono-allelic expression confirmed complete skewing of X-inactivation. Consequently, significantly enhanced MECP2 mRNA levels were observed. We hypothesize that the cause for the complete skewing is due to a more harmful mutation on the other X chromosome, thereby forcing the MECP2 duplication to become active. However, we could not unequivocally identify such a second mutation by array-CGH or exome sequencing. Our data underline that, like in males, increased MECP2 dosage in females can contribute to ID too, which should be taken into account in diagnostics.


Asunto(s)
Regulación de la Expresión Génica , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Inactivación del Cromosoma X/genética , Adolescente , Niño , Hibridación Genómica Comparativa , Exoma/genética , Femenino , Duplicación de Gen , Perfilación de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Repeticiones de Microsatélite/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de ADN
11.
Am J Med Genet A ; 164A(8): 1947-52, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24737742

RESUMEN

Genomic duplications of varying lengths at Xq26-q27 involving SOX3 have been described in families with X-linked hypopituitarism. Using array-CGH we detected a 1.1 Mb microduplication at Xq27 in a large family with three males suffering from X-linked hypopituitarism. The duplication was mapped from 138.7 to 139.8 Mb, harboring only two annotated genes, SOX3 and ATP11C, and was shown to be a direct tandem copy number gain. Unexpectedly, the microduplication did not fully segregate with the disease in this family suggesting that SOX3 duplications have variable penetrance for X-linked hypopituitarism. In the same family, a female fetus presenting with a neural tube defect was also shown to carry the SOX3 copy number gain. Since we also demonstrated increased SOX3 mRNA levels in amnion cells derived from an unrelated t(X;22)(q27;q11) female fetus with spina bifida, we propose that increased levels of SOX3 could be a risk factor for neural tube defects.


Asunto(s)
Dosificación de Gen , Genes Ligados a X , Hipopituitarismo/genética , Defectos del Tubo Neural/genética , Factores de Transcripción SOXB1/genética , Adolescente , Adulto , Duplicación Cromosómica , Mapeo Cromosómico , Segregación Cromosómica , Cromosomas Humanos X , Hibridación Genómica Comparativa , Femenino , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite/genética , Linaje , ARN Mensajero/genética , Factores de Riesgo , Adulto Joven
12.
Nucleic Acids Res ; 40(22): 11477-89, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23066103

RESUMEN

Telomere position effect (TPE) is the influence of telomeres on subtelomeric epigenetic marks and gene expression. Previous studies suggested that TPE depends on genetic background. As these analyses were performed on different chromosomes, cell types and species, it remains unclear whether TPE represents a chromosome-rather than genetic background-specific regulation. We describe the development of a Linear Human Artificial Chromosome (L-HAC) as a new tool for telomere studies. The L-HAC was generated through the Cre-loxP-mediated addition of telomere ends to an existing circular HAC (C-HAC). As it can be transferred to genetically distinct cell lines and animal models the L-HAC enables the study of TPE in an unprecedented manner. The HAC was relocated to four telomerase-positive cell lines via microcell-mediated chromosome transfer and subsequently to mice via blastocyst injection of L-HAC(+)-ES-cells. We could show consistent genetic background-dependent adaptation of telomere length and telomere-associated de novo subtelomeric DNA methylation in mouse ES-R1 cells as well as in mice. Expression of the subtelomeric neomycin gene was inversely correlated with telomere length and subtelomeric methylation. We thus provide a new tool for functional telomere studies and provide strong evidence that telomere length, subtelomeric chromatin marks and expression of subtelomeric genes are genetic background dependent.


Asunto(s)
Efectos de la Posición Cromosómica , Cromosomas Artificiales Humanos , Homeostasis del Telómero , Telómero/fisiología , Animales , Células Cultivadas , Cromatina/metabolismo , Cricetinae , Metilación de ADN , Humanos , Ratones , Ratones Endogámicos BALB C
13.
Hum Genet ; 132(10): 1177-85, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23783460

RESUMEN

Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A. Here, we report on overlapping microdeletions at Xq24 that do not include UBE2A or affect its expression, in patients with non-syndromic ID plus some additional features from three unrelated families. The smallest region of overlap, confirmed by junction sequencing, harbors two members of the mitochondrial solute carrier family 25, SLC25A5 and SLC25A43. However, identification of an intragenic microdeletion including SLC25A43 but not SLC25A5 in a healthy boy excluded a role for SLC25A43 in cognition. Therefore, our findings point to SLC25A5 as a novel gene for non-syndromic ID. This highly conserved gene is expressed ubiquitously with high levels in cortex and hippocampus, and a presumed role in mitochondrial exchange of ADP/ATP. Our data indicate that SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions.


Asunto(s)
Translocador 2 del Nucleótido Adenina/metabolismo , Deleción Cromosómica , Cromosomas Humanos X/genética , Discapacidad Intelectual/genética , Mitocondrias/metabolismo , Translocador 2 del Nucleótido Adenina/genética , Elementos Alu , Secuencia de Bases , Encéfalo/metabolismo , Encéfalo/patología , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Heterocigoto , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Mitocondrias/genética , Datos de Secuencia Molecular , Linaje , Inactivación del Cromosoma X
14.
Blood ; 117(15): 4056-64, 2011 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-21325169

RESUMEN

The genetics of classical Hodgkin lymphoma (cHL) is poorly understood. The finding of a JAK2-involving t(4;9)(q21;p24) in 1 case of cHL prompted us to characterize this translocation on a molecular level and to determine the prevalence of JAK2 rearrangements in cHL. We showed that the t(4;9)(q21;p24) leads to a novel SEC31A-JAK2 fusion. Screening of 131 cHL cases identified 1 additional case with SEC31A-JAK2 and 2 additional cases with rearrangements involving JAK2. We demonstrated that SEC31A-JAK2 is oncogenic in vitro and acts as a constitutively activated tyrosine kinase that is sensitive to JAK inhibitors. In vivo, SEC31A-JAK2 was found to induce a T-lymphoblastic lymphoma or myeloid phenotype in a murine bone marrow transplantation model. Altogether, we identified SEC31A-JAK2 as a chromosomal aberration characteristic for cHL and provide evidence that JAK2 rearrangements occur in a minority of cHL cases. Given the proven oncogenic potential of this novel fusion, our studies provide new insights into the pathogenesis of cHL and indicate that in at least some cases, constitutive activation of the JAK/STAT pathway is caused by JAK2 rearrangements. The finding that SEC31A-JAK2 responds to JAK inhibitors indicates that patients with cHL and JAK2 rearrangements may benefit from targeted therapies.


Asunto(s)
Reordenamiento Génico/genética , Enfermedad de Hodgkin/genética , Janus Quinasa 2/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Transporte Vesicular/genética , Adulto , Anciano de 80 o más Años , Animales , Trasplante de Médula Ósea , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 9 , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Células HEK293 , Enfermedad de Hodgkin/epidemiología , Humanos , Masculino , Ratones , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prevalencia , Proteínas Tirosina Quinasas/metabolismo , Translocación Genética , Adulto Joven
15.
Cancer Cell ; 7(4): 387-97, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15837627

RESUMEN

Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.


Asunto(s)
Mutación Missense/genética , Policitemia Vera/genética , Mielofibrosis Primaria/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Trombocitemia Esencial/genética , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Activación Enzimática/genética , Femenino , Genotipo , Granulocitos/metabolismo , Heterocigoto , Homocigoto , Humanos , Janus Quinasa 2 , Masculino , Persona de Mediana Edad , Mitosis/genética , Modelos Moleculares , Mucosa Bucal/metabolismo , Fosforilación , Mielofibrosis Primaria/complicaciones , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Recombinación Genética/genética , Transfección
16.
Proc Natl Acad Sci U S A ; 107(39): 16910-5, 2010 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-20837533

RESUMEN

We present an allele-specific copy number analysis of the in vivo breast cancer genome. We describe a unique bioinformatics approach, ASCAT (allele-specific copy number analysis of tumors), to accurately dissect the allele-specific copy number of solid tumors, simultaneously estimating and adjusting for both tumor ploidy and nonaberrant cell admixture. This allows calculation of "ASCAT profiles" (genome-wide allele-specific copy-number profiles) from which gains, losses, copy number-neutral events, and loss of heterozygosity (LOH) can accurately be determined. In an early-stage breast carcinoma series, we observe aneuploidy (>2.7n) in 45% of the cases and an average nonaberrant cell admixture of 49%. By aggregation of ASCAT profiles across our series, we obtain genomic frequency distributions of gains and losses, as well as genome-wide views of LOH and copy number-neutral events in breast cancer. In addition, the ASCAT profiles reveal differences in aberrant tumor cell fraction, ploidy, gains, losses, LOH, and copy number-neutral events between the five previously identified molecular breast cancer subtypes. Basal-like breast carcinomas have a significantly higher frequency of LOH compared with other subtypes, and their ASCAT profiles show large-scale loss of genomic material during tumor development, followed by a whole-genome duplication, resulting in near-triploid genomes. Finally, from the ASCAT profiles, we construct a genome-wide map of allelic skewness in breast cancer, indicating loci where one allele is preferentially lost, whereas the other allele is preferentially gained. We hypothesize that these alternative alleles have a different influence on breast carcinoma development.


Asunto(s)
Neoplasias de la Mama/genética , Carcinoma/genética , Dosificación de Gen , Genes Relacionados con las Neoplasias , Genoma Humano , Alelos , Femenino , Humanos , Ploidias
17.
Nat Genet ; 36(10): 1084-9, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15361874

RESUMEN

In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. Here we describe the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib.


Asunto(s)
Genes abl , Leucemia-Linfoma de Células T del Adulto/genética , Proteínas de Complejo Poro Nuclear/genética , Plásmidos/genética , Secuencia de Aminoácidos , Fusión Artificial Génica , Secuencia de Bases , Benzamidas , Línea Celular Tumoral , Cromosomas Humanos Par 9/genética , ADN de Neoplasias/genética , Inhibidores Enzimáticos/uso terapéutico , Amplificación de Genes , Humanos , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/enzimología , Datos de Secuencia Molecular , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Pirimidinas/uso terapéutico
18.
Am J Hum Genet ; 85(6): 809-22, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20004760

RESUMEN

We report on the identification of a 0.3 Mb inherited recurrent but variable copy-number gain at Xq28 in affected males of four unrelated families with X-linked mental retardation (MR). All aberrations segregate with the disease in the families, and the carrier mothers show nonrandom X chromosome inactivation. Tiling Xq28-region-specific oligo array revealed that all aberrations start at the beginning of the low copy repeat LCR-K1, at position 153.20 Mb, and end just distal to LCR-L2, at 153.54 Mb. The copy-number gain always includes 18 annotated genes, of which RPL10, ATP6AP1 and GDI1 are highly expressed in brain. From these, GDI1 is the most likely candidate gene. Its copy number correlates with the severity of clinical features, because it is duplicated in one family with nonsyndromic moderate MR, is triplicated in males from two families with mild MR and additional features, and is present in five copies in a fourth family with a severe syndromic form of MR. Moreover, expression analysis revealed copy-number-dependent increased mRNA levels in affected patients compared to control individuals. Interestingly, analysis of the breakpoint regions suggests a recombination mechanism that involves two adjacent but different sets of low copy repeats. Taken together, our data strongly suggest that an increased expression of GDI1 results in impaired cognition in a dosage-dependent manner. Moreover, these data also imply that a copy-number gain of an individual gene present in the larger genomic aberration that leads to the severe MECP2 duplication syndrome can of itself result in a clinical phenotype as well.


Asunto(s)
Cromosomas Humanos X , Dosificación de Gen , Discapacidad Intelectual/genética , Recombinación Genética , Adulto , Encéfalo/metabolismo , Niño , Preescolar , Aberraciones Cromosómicas , Mapeo Cromosómico , Femenino , Humanos , Masculino , Modelos Genéticos , Hibridación de Ácido Nucleico , Linaje , Fenotipo
19.
PLoS Biol ; 7(2): e40, 2009 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-19243220

RESUMEN

The acquisition of terminal cell fate and onset of differentiation are instructed by cell type-specific master control genes. Loss of differentiation is frequently observed during cancer progression, but the underlying causes and mechanisms remain poorly understood. We tested the hypothesis that master regulators of differentiation may be key regulators of tumor formation. Using loss- and gain-of-function analyses in Drosophila, we describe a critical anti-oncogenic function for the atonal transcription factor in the fly retina, where atonal instructs tissue differentiation. In the tumor context, atonal acts by regulating cell proliferation and death via the JNK stress response pathway. Combined with evidence that atonal's mammalian homolog, ATOH1, is a tumor suppressor gene, our data support a critical, evolutionarily conserved, function for ato in oncogenesis.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Transformación Celular Neoplásica/genética , Drosophila , Neoplasias del Ojo/genética , Regulación del Desarrollo de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteínas del Tejido Nervioso/genética , Animales , Apoptosis/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Tipificación del Cuerpo/genética , Diferenciación Celular/genética , Drosophila/embriología , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Neoplasias del Ojo/metabolismo , Silenciador del Gen , Proteínas del Tejido Nervioso/metabolismo , Organismos Modificados Genéticamente , Retina/citología , Retina/embriología
20.
PLoS Biol ; 7(2): e39, 2009 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-19243219

RESUMEN

Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo. Genetic knockouts in mouse and molecular analyses in the mouse and in human cancer cell lines support a tumor suppressor function for ATOH1. ATOH1 antagonizes tumor formation and growth by regulating proliferation and apoptosis, likely via activation of the Jun N-terminal kinase signaling pathway. Furthermore, colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations. Our data indicate that ATOH1 may be an early target for oncogenic mutations in tissues where it instructs cellular differentiation.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinoma de Células de Merkel/genética , Neoplasias Colorrectales/genética , Genes Supresores de Tumor/fisiología , Neoplasias Cutáneas/genética , Animales , Apoptosis/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Carcinoma de Células de Merkel/metabolismo , Carcinoma de Células de Merkel/patología , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , Regulación Neoplásica de la Expresión Génica , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Proteínas Quinasas JNK Activadas por Mitógenos , Masculino , Ratones , Ratones Noqueados , Mutación , Transducción de Señal , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología
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