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1.
Neurobiol Lang (Camb) ; 3(4): 515-537, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-37215340

RESUMEN

Recent mechanistic models argue for a key role of rhythm processing in both speech production and speech perception. Patients with the non-fluent variant (NFV) of primary progressive aphasia (PPA) with apraxia of speech (AOS) represent a specific study population in which this link can be examined. Previously, we observed impaired rhythm processing in NFV with AOS. We hypothesized that a shared neurocomputational mechanism structures auditory input (sound and speech) and output (speech production) in time, a "temporal scaffolding" mechanism. Since considerable white matter damage is observed in NFV, we test here whether white matter changes are related to impaired rhythm processing. Forty-seven participants performed a psychoacoustic test battery: 12 patients with NFV and AOS, 11 patients with the semantic variant of PPA, and 24 cognitively intact age- and education-matched controls. Deformation-based morphometry was used to test whether white matter volume correlated to rhythmic abilities. In 34 participants, we also obtained tract-based metrics of the left Aslant tract, which is typically damaged in patients with NFV. Nine out of 12 patients with NFV displayed impaired rhythmic processing. Left frontal white matter atrophy adjacent to the supplementary motor area (SMA) correlated with poorer rhythmic abilities. The structural integrity of the left Aslant tract also correlated with rhythmic abilities. A colocalized and perhaps shared white matter substrate adjacent to the SMA is associated with impaired rhythmic processing and motor speech impairment. Our results support the existence of a temporal scaffolding mechanism structuring perceptual input and speech output.

2.
Neurobiol Aging ; 88: 71-82, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31955981

RESUMEN

Primary progressive aphasia (PPA) is an overarching term for a heterogeneous group of neurodegenerative diseases which affect language processing. Impaired picture naming has been linked to atrophy of the anterior temporal lobe in the semantic variant of PPA. Although atrophy of the anterior temporal lobe proposedly impairs picture naming by undermining access to semantic knowledge, picture naming also entails object recognition and lexical retrieval. Using multivariate analysis, we investigated whether cortical atrophy relates to different types of naming errors generated during picture naming in 43 PPA patients (13 semantic, 9 logopenic, 11 nonfluent, and 10 mixed variant). Omissions were associated with atrophy of the anterior temporal lobes. Semantic errors, for example, mistaking a rhinoceros for a hippopotamus, were associated with atrophy of the left mid and posterior fusiform cortex and the posterior middle and inferior temporal gyrus. Semantic errors and atrophy in these regions occurred in each PPA subtype, without major between-subtype differences. We propose that pathological changes to neural mechanisms associated with semantic errors occur across the PPA spectrum.


Asunto(s)
Afasia Progresiva Primaria/diagnóstico , Afasia Progresiva Primaria/psicología , Pruebas Neuropsicológicas , Lóbulo Temporal/patología , Anciano , Afasia Progresiva Primaria/etiología , Afasia Progresiva Primaria/patología , Atrofia , Comprensión , Femenino , Humanos , Lenguaje , Masculino , Persona de Mediana Edad , Análisis Multivariante , Semántica
4.
Brain ; 139(Pt 6): 1817-29, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27060523

RESUMEN

The extent to which non-linguistic auditory processing deficits may contribute to the phenomenology of primary progressive aphasia is not established. Using non-linguistic stimuli devoid of meaning we assessed three key domains of auditory processing (pitch, timing and timbre) in a consecutive series of 18 patients with primary progressive aphasia (eight with semantic variant, six with non-fluent/agrammatic variant, and four with logopenic variant), as well as 28 age-matched healthy controls. We further examined whether performance on the psychoacoustic tasks in the three domains related to the patients' speech and language and neuropsychological profile. At the group level, patients were significantly impaired in the three domains. Patients had the most marked deficits within the rhythm domain for the processing of short sequences of up to seven tones. Patients with the non-fluent variant showed the most pronounced deficits at the group and the individual level. A subset of patients with the semantic variant were also impaired, though less severely. The patients with the logopenic variant did not show any significant impairments. Significant deficits in the non-fluent and the semantic variant remained after partialling out effects of executive dysfunction. Performance on a subset of the psychoacoustic tests correlated with conventional verbal repetition tests. In sum, a core central auditory impairment exists in primary progressive aphasia for non-linguistic stimuli. While the non-fluent variant is clinically characterized by a motor speech deficit (output problem), perceptual processing of tone sequences is clearly deficient. This may indicate the co-occurrence in the non-fluent variant of a deficit in working memory for auditory objects. Parsimoniously we propose that auditory timing pathways are altered, which are used in common for processing acoustic sequence structure in both speech output and acoustic input.


Asunto(s)
Afasia Progresiva Primaria/fisiopatología , Percepción Auditiva/fisiología , Psicoacústica , Anciano , Afasia Progresiva Primaria/diagnóstico , Afasia Progresiva Primaria/diagnóstico por imagen , Estudios de Casos y Controles , Señales (Psicología) , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas
5.
Cereb Cortex ; 26(1): 358-73, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25452579

RESUMEN

Word finding symptoms are frequent early in the course of Alzheimer's disease and relate principally to functional changes in left posterior temporal cortex. In cognitively intact older adults, we examined whether amyloid load affects the network for language and associative-semantic processing. Fifty-six community-recruited subjects (52-74 years), stratified for apolipoprotein E and brain-derived neurotrophic factor genotype, received a neurolinguistic assessment, (18)F-flutemetamol positron emission tomography, and a functional MRI of the associative-semantic system. The primary measure of amyloid load was the cerebral-to-cerebellar gray matter standardized uptake value ratio in a composite cortical volume of interest (SUVR(comp)). The primary outcome analysis consisted of a whole-brain voxelwise linear regression between SUVR(comp) and fMRI response during associative-semantic versus visuoperceptual processing. Higher activity in one region, the posterior left middle temporal gyrus, correlated positively with increased amyloid load. The correlation remained significant when only the word conditions were contrasted but not for pictures. According to a stepwise linear regression analysis, offline naming reaction times correlated positively with SUVR(comp). A binary classification into amyloid-positive and amyloid-negative cases confirmed our findings. The left posterior temporal activity increase may reflect higher demands for semantic control in the presence of a higher amyloid burden.


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Encéfalo/fisiopatología , Disfunción Cognitiva/fisiopatología , Lenguaje , Enfermedad de Alzheimer/diagnóstico , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico , Humanos , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Semántica
6.
J Neurosci ; 35(37): 12673-92, 2015 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-26377458

RESUMEN

Posterior cortical atrophy (PCA) is a rare focal neurodegenerative syndrome characterized by progressive visuoperceptual and visuospatial deficits, most often due to atypical Alzheimer's disease (AD). We applied insights from basic visual neuroscience to analyze 3D shape perception in humans affected by PCA. Thirteen PCA patients and 30 matched healthy controls participated, together with two patient control groups with diffuse Lewy body dementia (DLBD) and an amnestic-dominant phenotype of AD, respectively. The hierarchical study design consisted of 3D shape processing for 4 cues (shading, motion, texture, and binocular disparity) with corresponding 2D and elementary feature extraction control conditions. PCA and DLBD exhibited severe 3D shape-processing deficits and AD to a lesser degree. In PCA, deficient 3D shape-from-shading was associated with volume loss in the right posterior inferior temporal cortex. This region coincided with a region of functional activation during 3D shape-from-shading in healthy controls. In PCA patients who performed the same fMRI paradigm, response amplitude during 3D shape-from-shading was reduced in this region. Gray matter volume in this region also correlated with 3D shape-from-shading in AD. 3D shape-from-disparity in PCA was associated with volume loss slightly more anteriorly in posterior inferior temporal cortex as well as in ventral premotor cortex. The findings in right posterior inferior temporal cortex and right premotor cortex are consistent with neurophysiologically based models of the functional anatomy of 3D shape processing. However, in DLBD, 3D shape deficits rely on mechanisms distinct from inferior temporal structural integrity. SIGNIFICANCE STATEMENT: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visuoperceptual dysfunction and most often an atypical presentation of Alzheimer's disease (AD) affecting the ventral and dorsal visual streams rather than the medial temporal system. We applied insights from fundamental visual neuroscience to analyze 3D shape perception in PCA. 3D shape-processing deficits were affected beyond what could be accounted for by lower-order processing deficits. For shading and disparity, this was related to volume loss in regions previously implicated in 3D shape processing in the intact human and nonhuman primate brain. Typical amnestic-dominant AD patients also exhibited 3D shape deficits. Advanced visual neuroscience provides insight into the pathogenesis of PCA that also bears relevance for vision in typical AD.


Asunto(s)
Corteza Cerebral/patología , Percepción de Forma/fisiología , Enfermedades Neurodegenerativas/fisiopatología , Anciano , Agnosia/fisiopatología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Atrofia , Ceguera/etiología , Ceguera/fisiopatología , Mapeo Encefálico , Corteza Cerebral/fisiopatología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Percepción de Movimiento/fisiología , Corteza Motora/patología , Corteza Motora/fisiopatología , Enfermedades Neurodegenerativas/patología , Pruebas Neuropsicológicas , Tamaño de los Órganos , Tomografía de Emisión de Positrones , Lóbulo Temporal/patología , Lóbulo Temporal/fisiopatología
7.
PLoS One ; 9(12): e115215, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25500823

RESUMEN

Graph analysis is a promising tool to quantify brain connectivity. However, an essential requirement is that the graph measures are reproducible and robust. We have studied the reproducibility and robustness of various graph measures in group based and in individual binary and weighted networks derived from a task fMRI experiment during explicit associative-semantic processing of words and pictures. The nodes of the network were defined using an independent study and the connectivity was based on the partial correlation of the time series between any pair of nodes. The results showed that in case of binary networks, global graph measures exhibit a good reproducibility and robustness for networks which are not too sparse and these figures of merit depend on the graph measure and on the density of the network. Furthermore, group based binary networks should be derived from groups of sufficient size and the lower the density the more subjects are required to obtain robust values. Local graph measures are very variable in terms of reproducibility and should be interpreted with care. For weighted networks, we found good reproducibility (average test-retest variability <5% and ICC values >0.4) when using subject specific networks and this will allow us to relate network properties to individual subject information.


Asunto(s)
Conectoma/métodos , Imagen por Resonancia Magnética/métodos , Modelos Neurológicos , Factores de Edad , Anciano , Algoritmos , Conectoma/normas , Humanos , Imagen por Resonancia Magnética/normas , Masculino , Memoria/fisiología , Persona de Mediana Edad , Red Nerviosa/fisiología , Reproducibilidad de los Resultados
8.
Neuropsychologia ; 62: 163-74, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25080190

RESUMEN

We investigated the critical contribution of right ventral occipitotemporal cortex to knowledge of visual and functional-associative attributes of biological and non-biological entities and how this relates to category-specificity during confrontation naming. In a consecutive series of 7 patients with lesions confined to right ventral occipitotemporal cortex, we conducted an extensive assessment of oral generation of visual-sensory and functional-associative features in response to the names of biological and nonbiological entities. Subjects also performed a confrontation naming task for these categories. Our main novel finding related to a unique case with a small lesion confined to right medial fusiform gyrus who showed disproportionate naming impairment for nonbiological versus biological entities, specifically for tools. Generation of visual and functional-associative features was preserved for biological and non-biological entities. In two other cases, who had a relatively small posterior lesion restricted to primary visual and posterior fusiform cortex, retrieval of visual attributes was disproportionately impaired compared to functional-associative attributes, in particular for biological entities. However, these cases did not show a category-specific naming deficit. Two final cases with the largest lesions showed a classical dissociation between biological versus nonbiological entities during naming, with normal feature generation performance. This is the first lesion-based evidence of a critical contribution of the right medial fusiform cortex to tool naming. Second, dissociations along the dimension of attribute type during feature generation do not co-occur with category-specificity during naming in the current patient sample.


Asunto(s)
Lesiones Encefálicas/patología , Conocimiento , Lenguaje , Recuerdo Mental/fisiología , Lóbulo Occipital/patología , Semántica , Lóbulo Temporal/patología , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Lateralidad Funcional/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Agudeza Visual , Pruebas del Campo Visual
9.
Neuroimage Clin ; 2: 512-20, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24179803

RESUMEN

Aside from apolipoprotein E (APOE), genetic risk factors for ß amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimer's disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects ß amyloid burden and the relationship between ß amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was measured by means of (18)F-flutemetamol PET in 64 community-recruited cognitively intact individuals (mean age 66, S.D. 5.1). Recruitment was stratified according to a factorial design with APOE (ε4 allele present vs absent) and BDNF (met allele at codon 66 present vs absent) as factors. Individuals in the four resulting cells were matched by the number of cases, age, and gender. Among the APOE ε4 carriers, BDNF met positive subjects had a significantly higher amyloid load than BDNF met negative subjects, while BDNF met carrier status did not have an effect in APOE ε4 noncarriers. This interaction effect was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. In the APOE ε4/BDNF met carriers, a significant inverse relationship existed between episodic memory scores and amyloid burden but not in any of the other groups. This hypothesis-generating experiment highlights a potential role of BDNF polymorphisms in the preclinical phase of ß amyloid deposition and also suggests that BDNF codon 66 polymorphisms may influence resilience against ß amyloid-related effects on cognition.

10.
PLoS One ; 6(10): e26311, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22039459

RESUMEN

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (N = 27) and telomeric rearrangements (N = 15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (N = 39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis.


Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 1 , Proteínas de Unión al ADN/genética , Neoplasias Hematológicas/genética , Factores de Transcripción/genética , Línea Celular , Humanos , Hibridación Fluorescente in Situ , Polimorfismo de Nucleótido Simple , Telómero
11.
Br J Haematol ; 154(3): 337-48, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21569010

RESUMEN

Chromosomal rearrangements involving the MECOM (MDS1 and EVI1 complex) locus are recurrent genetic events in myeloid leukaemia and are associated with poor prognosis. In this study, we assessed the role of MECOM locus protein EVI1 in the transcriptional regulation of microRNAs (miRNAs) involved in the leukaemic phenotype. For this, we profiled expression of 366 miRNAs in 38 MECOM-rearranged patient samples, normal bone marrow controls and MECOM (EVI1) knock down/re-expression models. Cross-comparison of these miRNA expression profiling data showed that MECOM rearranged leukaemias are characterized by down regulation of MIR449A. Reconstitution of MIR449A expression in MECOM-rearranged cell line models induced apoptosis resulting in a strong decrease in cell viability. These effects might be mediated in part by MIR449A regulation of NOTCH1 and BCL2, which are shown here to be bona fide MIR449A targets. Finally, we confirmed that MIR449A repression is mediated through direct promoter occupation of the EVI1 transcriptional repressor. In conclusion, this study reveals MIR449A as a crucial direct target of the MECOM locus protein EVI1 involved in the pathogenesis of MECOM-rearranged leukaemias and unravels NOTCH1 and BCL2 as important novel targets of MIR449A. This EVI1-MIR449A-NOTCH1/BCL2 regulatory axis might open new possibilities for the development of therapeutic strategies in this poor prognostic leukaemia subgroup.


Asunto(s)
Proteínas de Unión al ADN/fisiología , Regulación hacia Abajo/fisiología , Leucemia/metabolismo , MicroARNs/biosíntesis , Proto-Oncogenes/fisiología , Factores de Transcripción/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Supervivencia Celular , Proteínas de Unión al ADN/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Lactante , Leucemia/genética , Leucemia/patología , Proteína del Locus del Complejo MDS1 y EV11 , MicroARNs/genética , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , ARN Neoplásico/genética , Receptor Notch1/biosíntesis , Receptor Notch1/fisiología , Elementos Reguladores de la Transcripción/fisiología , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas
12.
PLoS One ; 5(1): e8676, 2010 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-20084277

RESUMEN

Chromosomal rearrangements involving the EVI1 proto-oncogene are a recurrent finding in myeloid leukemias and are indicative of a poor prognosis. Rearrangements of the EVI1 locus are often associated with monosomy 7 or cytogenetic detectable deletions of part of 7q. As EVI1 overexpression alone is not sufficient to induce leukemia, loss of a 7q tumour suppressor gene might be a required cooperating event. To test this hypothesis, we performed high-resolution array comparative genomic hybridization analysis of twelve EVI1 overexpressing patients and three EVI1 deregulated cell lines to search for 7q submicroscopic deletions. This analysis lead to the delineation of two critical regions, one of 0.39 Mb on 7q35 containing the CNTNAP2 gene and one of 1.33 Mb on chromosome bands 7q35-q36 comprising nine genes in EVI1 deregulated cell lines. These findings open the way to further studies aimed at identifying the culprit EVI1 implicated tumour suppressor genes on 7q.


Asunto(s)
Cromosomas Humanos Par 7 , Proteínas de Unión al ADN/genética , Leucemia Mieloide/genética , Proto-Oncogenes/genética , Eliminación de Secuencia , Factores de Transcripción/genética , Secuencia de Bases , Línea Celular Tumoral , Cartilla de ADN , Humanos , Leucemia Mieloide/patología , Proteína del Locus del Complejo MDS1 y EV11 , Hibridación de Ácido Nucleico , Proto-Oncogenes Mas
13.
Br J Haematol ; 147(5): 686-90, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19775296

RESUMEN

Classical Hodgkin lymphoma (cHL) is characterized by the presence of malignant Hodgkin and Reed Sternberg (HRS) cells. The scarcity of tumour cells in lymphoma biopsies has hampered genetic analyses of HRS cells, including microRNA (miRNA) expression profiling. We determined the expression of 360 miRNAs in microdissected HRS cells from nine cHL patients. These miRNA profiles were compared to those from four cHL cell lines and CD77+ B-cells, yielding a distinct cHL signature of 12 over- and three underexpressed miRNAs. Our data suggest that miRNAs are implicated in the pathogenesis of Hodgkin lymphoma and prompt further investigations concerning their role in cHL.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Enfermedad de Hodgkin/genética , MicroARNs/genética , ARN Neoplásico/genética , Células de Reed-Sternberg/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Centro Germinal/inmunología , Enfermedad de Hodgkin/patología , Humanos , Microdisección , Trihexosilceramidas/análisis , Células Tumorales Cultivadas
14.
Genome Biol ; 10(6): R64, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19531210

RESUMEN

Gene expression analysis of microRNA molecules is becoming increasingly important. In this study we assess the use of the mean expression value of all expressed microRNAs in a given sample as a normalization factor for microRNA real-time quantitative PCR data and compare its performance to the currently adopted approach. We demonstrate that the mean expression value outperforms the current normalization strategy in terms of better reduction of technical variation and more accurate appreciation of biological changes.


Asunto(s)
MicroARNs/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normas , Algoritmos , Línea Celular Tumoral , Regulación hacia Abajo/genética , Reacciones Falso Positivas , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína Proto-Oncogénica N-Myc , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Estadísticas no Paramétricas
15.
Haematologica ; 93(12): 1903-7, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18815193

RESUMEN

Chromosomal translocations involving the EVI1 locus are a recurrent finding in myeloid leukemia and are associated with poor prognosis. In this study, we performed a detailed molecular characterization of the recurrent translocation t(3;17)(q26;q22) in 13 hematologic malignancies. The EVI1 gene locus was rearranged in all 13 patients and was associated with EVI1 overexpression. In 9 out of 13 patients, the 17q breakpoints clustered in a 250 kb region on band 17q22 encompassing the MSI2 (musashi homologue 2) gene. Expression analyses failed to demonstrate ectopic MSI2 expression or the presence of an MSI2/EVI1 fusion gene. In conclusion, we show for the first time that the t(3;17) is indeed a recurrent chromosomal aberration in myeloid malignancies. In keeping with findings in other recurrent 3q26 rearrangements, overexpression of the EVI1 gene appears to be the major contributor to leukemogenesis in patients with a t(3;17).


Asunto(s)
Proteínas de Unión al ADN/genética , Trastornos Mieloproliferativos/genética , Proto-Oncogenes/genética , Proteínas de Unión al ARN/genética , Factores de Transcripción/genética , Translocación Genética , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 3 , Proteínas de Unión al ADN/análisis , Humanos , Proteína del Locus del Complejo MDS1 y EV11 , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción/análisis
16.
BMC Cancer ; 8: 193, 2008 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-18613965

RESUMEN

BACKGROUND: Variant translocations t(9;22) occur in 5 to 10% of newly diagnosed CMLs and additional genetic changes are present in 60-80% of patients in blast crisis (BC). Here, we report on a CML patient in blast crisis presenting with a four-way variant t(9;22) rearrangement involving the EVI1 locus. METHODS: Dual-colour Fluorescence In Situ Hybridisation was performed to unravel the different cytogenetic aberrations. Expression levels of EVI1 and BCR/ABL1 were investigated using real-time quantitative RT-PCR. RESULTS: In this paper we identified a patient with a complex 4-way t(3;9;17;22) which, in addition to BCR/ABL1 gene fusion, also resulted in EVI1 rearrangement and overexpression. CONCLUSION: This report illustrates how a variant t(9;22) translocation can specifically target a second oncogene most likely contributing to the more aggressive phenotype of the disease. Molecular analysis of such variants is thus warranted to understand the phenotypic consequences and to open the way for combined molecular therapies in order to tackle the secondary oncogenic effect which is unresponsive to imatinib treatment.


Asunto(s)
Crisis Blástica/genética , Proteínas de Unión al ADN/genética , Proteínas de Fusión bcr-abl/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proto-Oncogenes/genética , Factores de Transcripción/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 3 , Cromosomas Humanos Par 9 , Análisis Citogenético , Proteínas de Unión al ADN/metabolismo , Proteínas de Fusión bcr-abl/biosíntesis , Genes abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Proteína del Locus del Complejo MDS1 y EV11 , Cromosoma Filadelfia , Factores de Transcripción/metabolismo , Activación Transcripcional
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