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1.
Leukemia ; 31(3): 565-572, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27694926

RESUMEN

Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, as the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3.8%), a frequency similar to CBFB-MYH11 fusion gene (4.0%). The most frequent NUP98 fusion gene partner is NSD1. These cases are homogeneous regarding their biological and clinical characteristics, and associated with bad prognosis only improved by bone marrow transplantation. We detailed the biological characteristics of these AML by exome sequencing which demonstrated few recurrent mutations (FLT3 ITD, WT1, CEBPA, NBPF14, BCR and ODF1). The analysis of the clonal structure in these cases suggests that the mutation order in the NUP98-rearranged pediatric AML begins with the NUP98 rearrangement leading to epigenetic dysregulations then followed by mutations of critical hematopoietic transcription factors and finally, activation of the FLT3 signaling pathway.


Asunto(s)
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteínas de Complejo Poro Nuclear/genética , Translocación Genética , Alelos , Biomarcadores de Tumor , Proteínas Potenciadoras de Unión a CCAAT/genética , Niño , Preescolar , Epigénesis Genética , Exoma , Femenino , Regulación Leucémica de la Expresión Génica , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Mutación , Proteínas de Fusión Oncogénica/genética , Pronóstico , Transducción de Señal , Proteínas WT1/genética , Tirosina Quinasa 3 Similar a fms/metabolismo
2.
J Thromb Haemost ; 14(3): 585-95, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26749169

RESUMEN

UNLABELLED: ESSENTIALS: The role of ATP-binding cassette transporter 1 (ABCA1) in platelet functions is poorly characterized. We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and two Tangier patients. ABCA1-deficient platelets exhibit reduced positive feedback loop mechanisms. This reduced reactivity is dependent on external environment and independent of hematopoietic ABCA1. BACKGROUND: The ATP-binding cassette transporter ABCA1 is required for the conversion of apolipoprotein A-1 to high-density lipoprotein (HDL), and its defect causes Tangier disease, a rare disorder characterized by an absence of HDL and accumulation of cholesterol in peripheral tissues. The role of ABCA1 in platelet functions remains poorly characterized. OBJECTIVE: To determine the role of ABCA1 in platelet functions and to clarify controversies concerning its implication in processes as fundamental as platelet phosphatidylserine exposure and control of platelet membrane lipid composition. METHODS AND RESULTS: We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and in two Tangier patients. We show that platelets in ABCA1-deficient mice are slightly larger in size and exhibit aggregation and secretion defects in response to low concentrations of thrombin and collagen. These platelets have normal cholesterol and major phospholipid composition, granule morphology, or calcium-induced phosphatidylserine exposure. Interestingly, ABCA1-deficient platelets display a reduction in positive feedback loop mechanisms, particularly in thromboxane A2 (TXA2) production. Hematopoietic chimera mice demonstrated that defective eicosanoids production, particularly TXA2, was primarily dependent on external environment and not on the hematopoietic ABCA1. Decreased aggregation and production of TXA2 and eicosanoids were also observed in platelets from Tangier patients. CONCLUSIONS: Absence of ABCA1 and low HDL level induce reduction of platelet reactivity by decreasing positive feedback loops, particularly TXA2 production through a hematopoietic ABCA1-independent mechanism.


Asunto(s)
Transportador 1 de Casete de Unión a ATP/deficiencia , Plaquetas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Enfermedad de Tangier/sangre , Transportador 1 de Casete de Unión a ATP/sangre , Transportador 1 de Casete de Unión a ATP/genética , Animales , Plaquetas/patología , Tamaño de la Célula , Modelos Animales de Enfermedad , Retroalimentación Fisiológica , Femenino , Predisposición Genética a la Enfermedad , Trasplante de Células Madre Hematopoyéticas , Hemostasis , Humanos , Lipoproteínas HDL/sangre , Masculino , Ratones Endogámicos DBA , Ratones Noqueados , Persona de Mediana Edad , Fenotipo , Agregación Plaquetaria , Enfermedad de Tangier/genética , Enfermedad de Tangier/patología , Trombosis/sangre , Trombosis/genética , Tromboxano A2/metabolismo , Factores de Tiempo
4.
Leukemia ; 26(11): 2384-9, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22513837

RESUMEN

Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from chimaeric fusion genes or point mutations such as BCR-ABL1 or JAK2 V617F. We report here the cloning and functional characterization of two novel fusion genes BCR-RET and FGFR1OP-RET in chronic myelomonocytic leukemia (CMML) cases generated by two balanced translocations t(10;22)(q11;q11) and t(6;10)(q27;q11), respectively. The two RET fusion genes leading to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. The RET fusion genes seem to constitutively mimic the same signaling pathway as RAS mutations frequently involved in CMML. One patient was treated with Sorafenib, a specific inhibitor of the RET TK function, and demonstrated cytological and clinical remissions.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Leucemia Mielomonocítica Crónica/patología , Monocitos/citología , Proteínas Proto-Oncogénicas c-ret/genética , Secuencia de Bases , Cartilla de ADN , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielomonocítica Crónica/genética , Mutación Puntual , Reacción en Cadena de la Polimerasa/métodos , Translocación Genética
5.
Leukemia ; 26(10): 2224-32, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22469780

RESUMEN

B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA, miR-125b-1, is overexpressed in B-ALL cases with the t(11;14)(q24;q32) translocation; therefore, we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was downregulated in B-ALL patients with the t(11;14)(q24;q32) translocation. Repression of Bright/ARID3a blocked differentiation and conferred a survival advantage to Ba/F3 cells under interleukin-3 starvation. In addition, overexpression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis by blockade of caspase activation by a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis.


Asunto(s)
Proteínas de Unión al ADN/fisiología , MicroARNs/fisiología , Células Precursoras de Linfocitos B/fisiología , Factores de Transcripción/fisiología , Diferenciación Celular , Proliferación Celular , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 14 , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Células Precursoras de Linfocitos B/citología , Translocación Genética , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/fisiología
7.
Leukemia ; 23(11): 1989-98, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19587702

RESUMEN

Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Unión al ADN/genética , Proteínas de Fusión bcr-abl/genética , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Proto-Oncogénicas/genética , Adolescente , Adulto , Antineoplásicos/uso terapéutico , Benzamidas , Ensayos Clínicos Fase II como Asunto , Dosificación de Gen , Reordenamiento Génico de Linfocito T/genética , Genómica , Haplotipos , Humanos , Mesilato de Imatinib , Cadenas Pesadas de Inmunoglobulina/genética , Inmunofenotipificación , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Piperazinas/uso terapéutico , Mutación Puntual , Factor de Transcripción 1 de la Leucemia de Células Pre-B , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Pronóstico , Estudios Prospectivos , Pirimidinas/uso terapéutico , Adulto Joven
8.
Cytogenet Cell Genet ; 92(3-4): 264-70, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11435699

RESUMEN

We report here the genomic and transcriptional characterization in mouse and man of a novel transporter of the ABCA subclass, named ABCA7. As it is the case for other ABCA genes, the predicted protein encoded by ABCA7 is a full symmetric transporter, highly conserved across species. The ABCA7 gene maps to human chromosome 19 and to the homologous region at band B4-C1 on mouse chromosome 10. The preferential expression of ABCA7 in the spleen, thymus, and fetal liver is consistent with the finding, in both human and mouse promoter, of sites targeted by lymphomyeloid-specific transcription factors. This suggests that ABCA7 may play a pivotal role in the developmental specification of hematopoietic cell lineages.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Exones/genética , Intrones/genética , Regiones Promotoras Genéticas/genética , Transportadoras de Casetes de Unión a ATP/química , Secuencia de Aminoácidos , Animales , Línea Celular , Cromosomas Humanos Par 19/genética , Secuencia Conservada/genética , ADN Complementario/genética , Humanos , Hibridación Fluorescente in Situ , Hígado/embriología , Hígado/metabolismo , Ratones , Datos de Secuencia Molecular , Especificidad de Órganos , ARN Mensajero/análisis , ARN Mensajero/genética , Mapeo de Híbrido por Radiación , Alineación de Secuencia , Homología de Secuencia de Ácido Nucleico , Bazo/metabolismo , Timo/metabolismo
9.
Nat Cell Biol ; 2(7): 399-406, 2000 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10878804

RESUMEN

ATP-binding-cassette transporter 1 (ABC1) has been implicated in processes related to membrane-lipid turnover. Here, using in vivo loss-of-function and in vitro gain-of-function models, we show that ABC1 promotes Ca2+-induced exposure of phosphatidylserine at the membrane, as determined by a prothrombinase assay, membrane microvesiculation and measurement of transbilayer redistribution of spin-labelled phospholipids. That ABC1 promotes engulfment of dead cells is shown by the impaired ability of ABC1-deficient macrophages to engulf apoptotic preys and by the acquisition of phagocytic behaviour by ABC1 transfectants. Release of membrane phospholipids and cholesterol to apo-AI, the protein core of the cholesterol-shuttling high-density lipoprotein (HDL) particle, is also ABC1-dependent. We propose that both the efficiency of apoptotic-cell engulfment and the efflux of cellular lipids depend on ABC1-induced perturbation of membrane phosphatidylserine turnover. Transient local exposure of anionic phospholipids in the outer membrane leaflet may be sufficient to alter the general properties of the membrane and thus influence discrete physiological functions.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Apoptosis , Glicoproteínas/metabolismo , Fagocitosis , Fosfatidilserinas/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Animales , Anexina A5/metabolismo , Apolipoproteína A-I/metabolismo , Calcio/farmacología , Membrana Celular/química , Membrana Celular/metabolismo , Células Cultivadas , Colesterol/metabolismo , Glicoproteínas/genética , Células HeLa , Humanos , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Macrófagos/citología , Macrófagos/inmunología , Ratones , Ratones Noqueados , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Marcadores de Spin , Tromboplastina/metabolismo , Timo/citología , Transfección
10.
Proc Natl Acad Sci U S A ; 97(8): 4245-50, 2000 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-10760292

RESUMEN

Recently, the human ATP-binding cassette transporter-1 (ABC1) gene has been demonstrated to be mutated in patients with Tangier disease. To investigate the role of the ABC1 protein in an experimental in vivo model, we used gene targeting in DBA-1J embryonic stem cells to produce an ABC1-deficient mouse. Expression of the murine Abc1 gene was ablated by using a nonisogenic targeting construct that deletes six exons coding for the first nucleotide-binding fold. Lipid profiles from Abc1 knockout (-/-) mice revealed an approximately 70% reduction in cholesterol, markedly reduced plasma phospholipids, and an almost complete lack of high density lipoproteins (HDL) when compared with wild-type littermates (+/+). Fractionation of lipoproteins by FPLC demonstrated dramatic alterations in HDL cholesterol (HDL-C), including the near absence of apolipoprotein AI. Low density lipoprotein (LDL) cholesterol (LDL-C) and apolipoprotein B were also significantly reduced in +/- and -/- compared with their littermate controls. The inactivation of the Abc1 gene led to an increase in the absorption of cholesterol in mice fed a chow or a high-fat and -cholesterol diet. Histopathologic examination of Abc1-/- mice at ages 7, 12, and 18 mo demonstrated a striking accumulation of lipid-laden macrophages and type II pneumocytes in the lungs. Taken together, these findings demonstrate that Abc1-/- mice display pathophysiologic hallmarks similar to human Tangier disease and highlight the capacity of ABC1 transporters to participate in the regulation of dietary cholesterol absorption.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Células Espumosas/citología , Glicoproteínas/genética , Lipoproteínas HDL/deficiencia , Mutación , Transportador 1 de Casete de Unión a ATP , Animales , Secuencia de Bases , Colesterol/sangre , Cartilla de ADN , Humanos , Lipoproteínas HDL/sangre , Ratones , Ratones Noqueados
11.
Nat Genet ; 24(2): 192-6, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10655069

RESUMEN

Mutations in the gene encoding ATP-binding cassette transporter 1 ( ABC1) have been reported in Tangier disease (TD), an autosomal recessive disorder that is characterized by almost complete absence of plasma high-density lipoprotein (HDL), deposition of cholesteryl esters in the reticulo-endothelial system (RES) and aberrant cellular lipid trafficking. We demonstrate here that mice with a targeted inactivation of Abc1 display morphologic abnormalities and perturbations in their lipoprotein metabolism concordant with TD. ABC1 is expressed on the plasma membrane and the Golgi complex, mediates apo-AI associated export of cholesterol and phospholipids from the cell, and is regulated by cholesterol flux. Structural and functional abnormalities in caveolar processing and the trans-Golgi secretory pathway of cells lacking functional ABC1 indicate that lipid export processes involving vesicular budding between the Golgi and the plasma membrane are severely disturbed.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Membrana Celular/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Aparato de Golgi/metabolismo , Metabolismo de los Lípidos , Enfermedad de Tangier/genética , Enfermedad de Tangier/metabolismo , Transportador 1 de Casete de Unión a ATP , Animales , Apoptosis , Plaquetas/metabolismo , Colesterol/sangre , Colesterol/metabolismo , HDL-Colesterol/sangre , Fibroblastos/metabolismo , Genotipo , Humanos , Mucosa Intestinal/patología , Mucosa Intestinal/ultraestructura , Intestino Delgado/patología , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Fosfolípidos/metabolismo , Triglicéridos/sangre
12.
Biochim Biophys Acta ; 1461(2): 395-404, 1999 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-10581369

RESUMEN

We describe here a subclass of mammalian ABC transporters, the ABCA subfamily. This is a unique group that, in contrast to any other human ABC transporters, lacks a structural counterpart in yeast. The structural hallmark of the ABCA subfamily is the presence of a stretch of hydrophobic amino acids thought to span the membrane within the putative regulatory (R) domain. As for today, four ABCA transporters have been fully characterised but 11 ABCA-encoding genes have been identified. ABCA-specific motifs in the nucleotide binding folds can be detected when analysing the conserved sequences among the different members. These motifs may reveal functional constraints exclusive to this group of ABC transporters.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/clasificación , Proteínas de Caenorhabditis elegans , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/química , Transportadoras de Casetes de Unión a ATP/genética , Secuencia de Aminoácidos , Animales , Proteínas Bacterianas/genética , Proteínas Portadoras/genética , Oftalmopatías/genética , Genoma , Glicoproteínas/genética , Humanos , Invertebrados , Datos de Secuencia Molecular , Nucleótidos/química
13.
Proc Natl Acad Sci U S A ; 96(22): 12685-90, 1999 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-10535983

RESUMEN

Tangier disease is characterized by low serum high density lipoproteins and a biochemical defect in the cellular efflux of lipids to high density lipoproteins. ABC1, a member of the ATP-binding cassette family, recently has been identified as the defective gene in Tangier disease. We report here the organization of the human ABC1 gene and the identification of a mutation in the ABC1 gene from the original Tangier disease kindred. The organization of the human ABC1 gene is similar to that of the mouse ABC1 gene and other related ABC genes. The ABC1 gene contains 49 exons that range in size from 33 to 249 bp and is over 70 kb in length. Sequence analysis of the ABC1 gene revealed that the proband for Tangier disease was homozygous for a deletion of nucleotides 3283 and 3284 (TC) in exon 22. The deletion results in a frameshift mutation and a premature stop codon starting at nucleotide 3375. The product is predicted to encode a nonfunctional protein of 1,084 aa, which is approximately half the size of the full-length ABC1 protein. The loss of a Mnl1 restriction site, which results from the deletion, was used to establish the genotype of the rest of the kindred. In summary, we report on the genomic organization of the human ABC1 gene and identify a frameshift mutation in the ABC1 gene of the index case of Tangier disease. These results will be useful in the future characterization of the structure and function of the ABC1 gene and the analysis of additional ABC1 mutations in patients with Tangier disease.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Glicoproteínas/genética , Enfermedad de Tangier/genética , Transportador 1 de Casete de Unión a ATP , Animales , Secuencia de Bases , ADN , Exones , Femenino , Humanos , Intrones , Masculino , Ratones , Linaje
14.
Eur J Hum Genet ; 6(6): 638-41, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9887385

RESUMEN

ALDR is one of the four genes encoding an ATP Binding Cassette (ABC) hemi-transporter of the peroxisomal membrane so far identified in mammalian cells. The best known of these is X-ALD, whose dysfunction has been causally associated with X-linked adrenoleukodystrophy. ALDR and X-ALD protein product are closely related and we show here that this striking conservation is maintained at the genomic level. Although extending to a larger genomic region, the organisation of the mouse ALDR gene mirrors exactly that of X-ALD. This supports further the hypothesis that among the four known peroxisomal ABC hemi-transporters ALDRP is the most likely candidate as a modifier contributing to the phenotypic variability of X-linked adrenoleukodystrophy.


Asunto(s)
Transportadoras de Casetes de Unión a ATP , Adrenoleucodistrofia/genética , Exones , Proteínas/genética , Subfamilia D de Transportadores de Casetes de Unión al ATP , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN Complementario , Ratones , Datos de Secuencia Molecular , Mapeo Restrictivo , Homología de Secuencia de Aminoácido , Cromosoma X
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