RESUMEN
Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a poor-risk entity, commonly associated with FLT3-ITD (internal tandem duplication). Allogeneic stem-cell tranplantation (allo-SCT) is recommended, although studies analysing the outcome of allo-SCT in this setting are lacking. We selected 195 patients with t(6;9) AML, who received a first allo-SCT between 2000 and 2016 from the EBMT (European Society for Blood and Marrow Transplantation) registry. Disease status at time of allo-SCT was the strongest independent prognostic factor, with a two-year leukaemia-free survival and relapse incidence of 57% and 19% in patients in CR1 (first complete remission), 34% and 33% in CR2 (second complete remission), and 24% and 49% in patients not in remission, respectively (P < 0·001). This study, which represents the largest one available in t(6;9) AML, supports the recommendation to submit these patients to allo-SCT in CR1.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 9/genética , Trasplante de Células Madre de Sangre del Cordón Umbilical , Leucemia Mieloide Aguda/terapia , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Oncogénicas/genética , Trasplante de Células Madre de Sangre Periférica , Proteínas de Unión a Poli-ADP-Ribosa/genética , Translocación Genética , Adulto , Aloinjertos , Cromosomas Humanos Par 6/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Supervivencia sin Enfermedad , Femenino , Duplicación de Gen , Enfermedad Injerto contra Huésped/etiología , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Inducción de Remisión , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fms/genéticaAsunto(s)
Cromosomas Humanos Par 6/genética , Leucemia Linfocítica Crónica de Células B/genética , Eliminación de Secuencia , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 6/ultraestructura , Progresión de la Enfermedad , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Tiempo de Tratamiento , Adulto JovenRESUMEN
The patient had been diagnosed with polycythemia vera (PV) in 1999, at the age of 61, according to the criteria of the Polycythemia Vera Study Group (PVSG) on the basis of the increased red cell mass by isotope determination, normal oxygen saturation, low plasma erythropoietin level, presence of endogenous erythroid colonies (EEC), and splenomegaly. Histopathology of bone marrow biopsy was also consistent with polycythemia vera with no evidence of increased reticulin fibrosis. A karyotype analysis was not performed at that time. He had been treated initially with phlebotomies and then with hydroxyurea with the aim to obtain a better control of hematocrit; he was under low-dose aspirin. In 2009, 10 years after the diagnosis, while the patient was still being treated with hydroxyurea and phlebotomies, he noticed worsening of general conditions and fatigue, and the appearance of night sweats; he also reported that his spleen volume had increased rapidly in the past few months. He complained of severe pruritus especially after (but not limited to) a shower. He was referred to our center for further evaluation. At presentation, his blood counts were as follows: hemoglobin 157 g/L, hematocrit 54.7%, leukocytes 13.1 × 109 /L, platelets 238 × 109 /L, LDH 856 U/L (normal upper limit, 250 U/L). Blood film examination showed neutrophilia (8.9 × 109 /L) but immature myeloid cells and nucleated erythroblasts were absent. The spleen was 14 cm below the left costal margin, the liver was at 4 cm below the right costal margin. He was found to harbor the JAK2V617F mutation with an allele burden of 85% and the circulating CD34⺠cell count was 14 × 106 /L. A bone marrow biopsy showed the presence of hyperplasia of myeloid and erythroid lineages, increased number of scattered megakarocytes without overt morphologic abnormalities; reticulin fibrosis was grade 1 according to the European classification. On these basis, we considered the patient as presenting the features of PV according to the 2008 WHO classification of myeloid neoplasms associated with grade 1 reticulin fibrosis.
Asunto(s)
Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 6/genética , Cariotipo , Policitemia Vera/genética , Translocación Genética , Deleción Cromosómica , Cromosomas Humanos Par 15/ultraestructura , Cromosomas Humanos Par 6/ultraestructura , Terapia Combinada , Progresión de la Enfermedad , Células Eritroides/patología , Humanos , Hidroxiurea/efectos adversos , Hidroxiurea/uso terapéutico , Hiperplasia , Hibridación Fluorescente in Situ , Janus Quinasa 2/genética , Masculino , Megacariocitos/patología , Persona de Mediana Edad , Células Mieloides/patología , Flebotomía , Mutación Puntual , Policitemia Vera/sangre , Policitemia Vera/complicaciones , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/patología , Policitemia Vera/terapia , Mielofibrosis Primaria/etiología , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patología , Reticulina/análisisRESUMEN
Chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) have an inherent tendency to progress to acute myeloid leukemia (AML). Using high-resolution SNP microarrays, we studied a total of 517 MPN and MDS patients in different disease stages, including 77 AML cases with previous history of MPN (N = 46) or MDS (N = 31). Frequent chromosomal deletions of variable sizes were detected, allowing the mapping of putative tumor suppressor genes involved in the leukemic transformation process. We detected frequent deletions on the short arm of chromosome 6 (del6p). The common deleted region on 6p mapped to a 1.1-Mb region and contained only the JARID2 gene--member of the polycomb repressive complex 2 (PRC2). When we compared the frequency of del6p between chronic and leukemic phase, we observed a strong association of del6p with leukemic transformation (P = 0.0033). Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex member SUZ12. As the frequency of point mutations in PRC2 members was found to be low, deletions were the main type of lesions targeting PRC2 complex members. Our study suggests an essential role of the PRC2 complex in the leukemic transformation of chronic myeloid disorders.
Asunto(s)
Transformación Celular Neoplásica/genética , Deleción Cromosómica , Cromosomas Humanos Par 6/ultraestructura , Genes Supresores de Tumor , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Proteínas de Neoplasias/fisiología , Proteínas del Tejido Nervioso/fisiología , Proteínas Supresoras de Tumor/fisiología , Enfermedad Aguda , Anciano , Proteínas Portadoras/genética , Aberraciones Cromosómicas , Mapeo Cromosómico , Cromosomas Humanos Par 6/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Genotipo , Humanos , Leucemia Mieloide/genética , Masculino , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Complejo Represivo Polycomb 2 , Proteínas del Grupo Polycomb , Proteínas Represoras/deficiencia , Proteínas Represoras/genética , Proteínas Represoras/fisiología , Análisis de Secuencia de ADN , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genéticaRESUMEN
Precursor T-cell acute lymphoblastic leukemia (T-ALL) in children represents a clinical challenge, because relapses are usually fatal. It is thus necessary to identify high-risk patients as early as possible to effectively individualize treatment. We aimed to define novel molecular risk markers in T-ALL and performed array-based comparative genomic hybridization (array-CGH) and expression analyses in 73 patients. We show that DNA copy-number changes are common in T-ALL and affect 70 of 73 (96%) patients. Notably, genomic imbalances predicted to down-regulate the TGF-beta or up-regulate the PI3K-AKT pathways are identified in 25 of 73 (34%) and 21 of 73 (29%) patients, suggesting that these pathways play key roles in T-ALL leukemogenesis. Furthermore, we identified a deletion at 6q15-16.1 in 9 of 73 (12%) of the patients, which predicts poor early treatment response. This deletion includes the CASP8AP2 gene, whose expression is shown to be down-regulated. The interaction of CASP8AP2 with CASP8 plays a crucial role in apoptotic regulation, suggesting a functional link between the clinical effect of the deletion and the molecular mode of action. The data presented here implicate the TGF-beta and PI3K-AKT pathways in T-ALL leukemogenesis and identify a subgroup of patients with CASP8AP2 deletions and poor early treatment response.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Deleción Cromosómica , Cromosomas Humanos Par 6/genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Transducción de Señal/genética , Adolescente , Niño , Preescolar , Cromosomas Humanos Par 6/ultraestructura , Hibridación Genómica Comparativa , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Femenino , Dosificación de Gen , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Fosfatidilinositol 3-Quinasas/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Pronóstico , Proteínas Proto-Oncogénicas c-akt/genética , Receptor Notch1/genética , Factor de Crecimiento Transformador beta/genética , Resultado del TratamientoRESUMEN
Reading disabilities (RDs) have been associated with chromosome 6p with recent studies pointing to two genes, DCDC2 and KIAA0319. In this study, markers across the 6p region were tested for association with RD. Our strongest findings were for association with markers in KIAA0319, although with the opposite alleles compared with a previous study. We also found association with markers in VMP, but not with DCDC2. Current evidence indicates that differential regulation of KIAA0319 and DCDC2 contributes to RD, thus we used chromatin immunoprecipitation coupled with genomic tiling arrays (ChIP-chip) to map acetylated histones, a molecular marker for regulatory elements, across a 500 kb genomic region covering the RD locus on 6p. This approach identified several regions marked by acetylated histones that mapped near associated markers, including intron 7 of DCDC2 and the 5' region of KIAA0319. The latter is located within the 70 kb region previously associated with differential expression of KIAA0319. Interestingly, five markers associated with RD in independent studies were also located within the 2.7 kb acetylated region, and six additional associated markers, including the most significant one in this study, were located within a 22 kb haplotype block that encompassed this region. Our data indicates that this putative regulatory region is a likely site of genetic variation contributing to RD in our sample, further narrowing the candidate region.
Asunto(s)
Dislexia/genética , Histonas/genética , Proteínas del Tejido Nervioso/genética , Regiones no Traducidas 3' , Mapeo Cromosómico , Cromosomas Humanos Par 6/ultraestructura , Salud de la Familia , Marcadores Genéticos , Variación Genética , Haplotipos , Humanos , Inmunoprecipitación , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Regiones Promotoras GenéticasRESUMEN
Neuritin 1 (NRN1), an activity-regulated gene with multiple roles in neurodevelopment and synaptic plasticity, is located within the 6p24-p25 interval on chromosome 6, previously identified as linked to a subtype of schizophrenia (SZ) characterized by pervasive cognitive deficit (CD). We have tested the effect of NRN1 sequence variation on susceptibility to SZ and on general cognitive ability in patients and non-psychiatric control subjects by re-sequencing the coding regions of NRN1 and its flanking sequences, and genotyping 19 single-nucleotide polymorphisms (SNPs) in 336 SZ patients and 172 healthy control individuals. All participants completed comprehensive neurocognitive assessment, including tests estimating premorbid/prior IQ and current IQ. Logistic regression analyses found no significant association for any of the 19 SNPs with SZ or its CD subtype. However, linear regression analysis gave significant association (P = 0.024 and P = 0.027 after correction for multiple testing) for polymorphisms rs1475157 and rs9405890 with current IQ in the patient group. In SZ, the rs1475157-rs9405890 haplotypes revealed a highly significant association with the abstraction component of current ("fluid") intelligence (P = 0.0014), and with percentage loss of IQ points between premorbid and current intelligence (P = 0.0041). Results in the control group were not significant after correction. This is the first analysis of association between variation in NRN1 and SZ. The findings suggest a role of NRN1 as a modifier of cognitive functioning in SZ, with implications for future research into the impact of the environment on the development and maintenance of "fluid" intelligence.
Asunto(s)
Neuropéptidos/genética , Polimorfismo Genético , Esquizofrenia/genética , Cromosomas Humanos Par 6/ultraestructura , Cognición , Femenino , Proteínas Ligadas a GPI/genética , Predisposición Genética a la Enfermedad , Humanos , Pruebas de Inteligencia , Masculino , Modelos Neurológicos , Plasticidad Neuronal , Fenotipo , Polimorfismo de Nucleótido Simple , Sinapsis/patologíaRESUMEN
In order to select compatible human leucocytes antigens (HLA) donors for bone marrow graft, all the members of 76 families were typed by serology for HLA class I (A and B locus) and class II (DR, DQ locus) by polymerase chain-reaction-sequence-specific primes (PCR-SSP). The HLA typing interpretation revealed the existence of crossing-over in major histocompatibility (CMH) regions for two families, AB and AT, with aplastic bone marrow. The study of crossing-over site has needed the genotyping of seven short tandem repeat (STR) markers located on the short arm of chromosome 6 (D6S291, D6S273, TNFa, C1.2.C, C3.2.11, D6S265, D6S276), using ABI Prism 310 sequencer. HLA and STR Haplotypic analysis enabled us to confirm the crossing-over between locus B and DR in AB family and between locus A and B in AT family. Based in this study, we recommend to be careful in the interpretation of the results of HLA typing between donors and recipients of bone marrow. Complementary investigations should be accomplished for studying genetic abnormalities, which would be involved in this pathology.
Asunto(s)
Anemia Aplásica/genética , Intercambio Genético , Complejo Mayor de Histocompatibilidad/genética , Anemia Aplásica/epidemiología , Anemia Aplásica/cirugía , Trasplante de Médula Ósea , Niño , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 6/ultraestructura , Consanguinidad , Femenino , Genes MHC Clase I , Genes MHC Clase II , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-DR/genética , Haplotipos/genética , Prueba de Histocompatibilidad , Humanos , Masculino , Recombinación Genética , Donantes de Tejidos , Túnez , Adulto JovenRESUMEN
Aggressive natural killer cell leukemia (ANKL) is a very rare condition and when reported occurs almost exclusively in adults. We report a pediatric case of ANKL that presented with hemophagocytic syndrome, preceding the onset of leukemia by 12 weeks. Clinical and laboratory findings are discussed, along with morphology, immunophenotyping and cytogenetics, as well as the association with Epstein-Barr virus (EBV). This case is noteworthy for the expression of CD8 on the malignant cells, the cytogenetic findings that include abnormalities of chromosomes 6 and 7, as well as the age of the patient.
Asunto(s)
Leucemia Linfocítica Granular Grande/complicaciones , Linfohistiocitosis Hemofagocítica/etiología , Aneuploidia , Antígenos CD8/análisis , Preescolar , Aberraciones Cromosómicas , Cromosomas Humanos Par 6/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Progresión de la Enfermedad , Infecciones por Virus de Epstein-Barr/complicaciones , Resultado Fatal , Humanos , Leucemia Linfocítica Granular Grande/diagnóstico , Leucemia Linfocítica Granular Grande/etnología , Masculino , Insuficiencia Multiorgánica/etiología , Infecciones Oportunistas/etiologíaRESUMEN
PURPOSE: Using fluorescence in situ hybridization (FISH) and high-density single nucleotide polymorphism (SNP) mapping genome array, we comparatively evaluated chromosome 3 status and other chromosomal aberrations within a series of choroidal melanomas biopsied by fine needle aspiration (FNAB). METHODS: Transscleral FNAB was performed in 59 patients (59 eyes) who had a clinical diagnosis of choroidal melanoma. Biopsies were processed for chromosome 3 status by centromeric interphase FISH, cytopathology, cell culture, and simultaneous genomic DNA and RNA mapping array analysis. RESULTS: FISH yielded chromosome 3 status in 38 of 59 (64%) eyes, while high-density SNP mapping array yielded chromosome 3 status in 43 of 59 (73%) eyes. Monosomy 3 was detected by FISH in 15 of 38 (39%) cases, and high-density SNP mapping array data confirmed the finding in 13 of the 15 cases. Furthermore, high-density SNP mapping array revealed five additional cases of significant chromosome 3 aberration not detected by FISH. High-density genomic mapping also provided detailed patterns of chromosomal gain and loss on chromosomes 1, 6, 8, and 9 which segregated into two groups characterized by either monosomy 3 or chromosome 6p gain. CONCLUSIONS: High-density SNP mapping array was better than FISH in detecting chromosome 3 aberrations and monosomy in our melanoma samples. More importantly, the mapping arrays detected additional patterns of chromosomal aberration, which suggest specific pathways for cytogenetic rearrangements in choroidal melanoma and may improve prognostic testing.
Asunto(s)
Neoplasias de la Coroides/genética , Cromosomas Humanos Par 3/genética , Melanoma/genética , Monosomía/diagnóstico , Biopsia con Aguja Fina , Neoplasias de la Coroides/patología , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 1/ultraestructura , Cromosomas Humanos Par 3/ultraestructura , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 6/ultraestructura , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 7/ultraestructura , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/ultraestructura , Análisis Citogenético/métodos , Perfilación de la Expresión Génica/métodos , Humanos , Hibridación Fluorescente in Situ/métodos , Cariotipificación/métodos , Melanoma/patología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Polimorfismo de Nucleótido Simple , Sensibilidad y EspecificidadRESUMEN
So far, only one variant translocation of the t(11;18)(q21;q21), the t(11;12;18) (q21;q13;q21), has been reported. We herein describe two new variant translocations, the t(6;18;11)(q24;q21;q21) and the t(11;14;18)(q21;q32;q21), occurring in mucosa-associated lymphoid tissue (MALT) lymphomas. In both cases, fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) revealed the presence of an 5'API2-3'MALT1 fusion product, encoded on the derivative chromosome 11. Exon 7 of API2 was fused with exon 5 of MALT1 in the t(11;14;18) and with exon 8 of MALT1 in the t(6;18;11). FISH revealed the involvement of the immunoglobulin locus in the t(11;14;18). Rapid amplification of cDNA ends (RACE)-PCR to detect the involved partner gene on 6q showed exclusively wild-type API2 and MALT1 sequences.
Asunto(s)
Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 6/genética , Exones/genética , Linfoma de Células B de la Zona Marginal/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Anciano , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 18/ultraestructura , Cromosomas Humanos Par 6/ultraestructura , Sistemas de Computación , Genes de Inmunoglobulinas , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Gástricas/genéticaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Médula Ósea/patología , Daunorrubicina/efectos adversos , Etopósido/efectos adversos , Leucemia Mieloide Aguda/inducido químicamente , Neoplasias Primarias Secundarias/inducido químicamente , Pancitopenia/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromosomas Humanos Par 6/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Terapia Combinada , Irradiación Craneana , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Eritropoyesis/efectos de los fármacos , Etopósido/administración & dosificación , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Quimioterapia de Mantención/efectos adversos , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/genética , Proteínas de Fusión Oncogénica/genética , Pancitopenia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/radioterapia , Translocación Genética , Vincristina/administración & dosificaciónRESUMEN
Inversions are infrequent events in hematological malignancies. We here report the cytogenetic, fluorescence in situ hybridization (FISH), and molecular studies of 2 patients diagnosed with mantle cell lymphoma (MCL) that showed inversions of chromosomes 2 and 6 as part of complex karyotypes. Both patients showed a cytogenetically identical inv(6)(p23q11) detected as a secondary aberration. In addition, both patients had a derivative chromosome 2 which originated by partial deletion of the short arm and a pericentric inversion with different breakpoints on the long arm: der(2)del(2)(p21)inv(2)(p21q11) and der(2)del(2)(p21)inv(2)(p21q13), respectively. The presence of t(11;14)(q13;q32) was confirmed by interphase FISH and by molecular study. Residual normal cells were found in both cases. The patients showed a different clinical evolution with a poor outcome for one case and a favorable course of the disease for the other one. The review of the literature in MCL showed a total of 9 inversions affecting different chromosomes. Considering that inversions are very infrequent events in MCL, our findings could be important for detecting genes potentially involved in development and/or progression of this aggressive non-Hodgkin lymphoma subtype.
Asunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 2 , Cromosomas Humanos Par 6 , Linfoma de Células del Manto/genética , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 2/ultraestructura , Cromosomas Humanos Par 6/ultraestructura , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Linfoma de Células del Manto/diagnóstico , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
The TEL/ETV6 gene is located at 12p13 and is frequently involved in chromosomal translocations in human malignancies usually resulting in the expression of fusion proteins between the amino terminal part of TEL, and either unrelated transcription factors or protein tyrosine kinases. We report here a novel gene named TELB which is located on human chromosomal band 6p21 and encodes a protein highly related to TEL. TELB is widely expressed in different tissues and, similarly to TEL encodes a sequence-specific transcriptional repressor.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Drosophila , Genes , Leucemia/genética , Proteínas Proto-Oncogénicas , Factores de Transcripción/genética , Secuencia de Aminoácidos , Animales , Linfoma de Burkitt/genética , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 6/ultraestructura , Subunidad alfa 2 del Factor de Unión al Sitio Principal , ADN Complementario/genética , ADN de Neoplasias/genética , Proteínas de Unión al ADN/biosíntesis , Drosophila melanogaster/genética , Exones/genética , Etiquetas de Secuencia Expresada , Proteínas del Ojo/genética , Regulación Leucémica de la Expresión Génica , Células HeLa , Humanos , Datos de Secuencia Molecular , Familia de Multigenes , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-ets , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/genética , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Factores de Transcripción/biosíntesis , Transcripción Genética , Transfección , Translocación Genética , Proteína ETS de Variante de Translocación 6RESUMEN
BACKGROUND AND OBJECTIVES: Many clinically important oncogenes and tumor suppressor genes have been identified through analysis of recurrent chromosomal rearrangements in acute leukemia. The contribution of sporadic rearrangements to malignancy is less clear and few have been mapped in detail. In this study we investigated the significance of novel translocations and inversions of 6q in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). DESIGN AND METHODS: Breakpoints of balanced 6q rearrangements were mapped in sequential fluorescent in situ hybridization (FISH) experiments with BAC and PAC clones in 11 patients. RESULTS: Six of seven breakpoints in ALL and two in a single case of AML were localized to within a 10.5 Mb hotspot at 6q22-q23 with five analyzed to the level of a single probe. In two cases of childhood T-ALL, both carrying a t(6;7)(q23;q32 through 36), split FISH signals were produced by adjacent PAC, mapping the breakpoints to within an approximately 150 Kb region containing the genes c-MYB and AHI1. Five similar rearrangements, four also in pediatric T ALL were identified in the literature. Other 6q22-q23 translocations mapped in detail interrupted regions containing no recognized genes. 6q breakpoints outside the q22-q23 region were widely dispersed and in two were mapped to positions overlapping the cloned fragile sites FRA6E and FRA6F. The involvement of MLL was demonstrated in one case with t(6;11)(q15;q23). INTERPRETATION AND CONCLUSIONS: We identified a new primary recurrent translocation t(6;7) (q22;q23 through q26) in pediatric T-ALL. Other translocations interrupting the 6q22-q23 breakpoint cluster region did not appear to be recurrent and may contribute to leukemogenesis through a novel mechanism. Key words; chromosome 6, translocation, c-Myb, AHI1.
Asunto(s)
Rotura Cromosómica , Inversión Cromosómica/genética , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 7/genética , Genes myb , Leucemia Mieloide/genética , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética/genética , Enfermedad Aguda , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras del Transporte Vesicular , Adolescente , Células de la Médula Ósea/ultraestructura , Niño , Preescolar , Bandeo Cromosómico , Cromosomas Humanos Par 6/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Células Clonales/patología , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Leucemia Mieloide/patología , Leucemia-Linfoma de Células T del Adulto/patología , Masculino , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologíaRESUMEN
Deletion of the long arm of human chromosome 6 in acute lymphoblastic leukemia (ALL) has been shown by cytogenetic studies in 4-11% of cases. To characterize further the region of deletion and to precisely establish its frequency, we studied loss of heterozygosity (LOH) in 120 children with ALL using polymorphic markers located from the 6q14-15 chromosomal band to the telomere. LOH was detected in eight patients. A single region of LOH, flanked distally by D6S1594 and proximally by D6S301 was detected. These DNA markers are separated by 6 cM and are approximately located at the 6q21-22 band. Our present results delineate a region that is likely to contain a tumor-suppressor gene involved in a subset of childhood ALLs.
Asunto(s)
Cromosomas Humanos Par 6/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Eliminación de Secuencia , Adolescente , Aneuploidia , Niño , Preescolar , Cromosomas Humanos Par 6/ultraestructura , Femenino , Genes Supresores de Tumor , Marcadores Genéticos , Heterocigoto , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Células Tumorales CultivadasRESUMEN
MUM1/IRF4 is a myeloma-associated oncogene transcriptionally activated as a result of t(6;14)(p25,q32) chromosomal translocation and by virtue of its juxtaposition to the immunoglobulin heavy chain gene (IgH) locus. When this oncogene becomes non-functional, no activated B/T lymphocytes and Ig secreting plasma cells are observed, suggesting that MUM1/IRF4 is crucial for lymphoid development. Its expression was analyzed in both reactive lymphoid and lymphoma tissues by means of an immunohistochemical technique using specific goat antiserum against MUM1/IRF4. This analysis detected a 50 kDa MUM1 product whose localization was restricted to the nuclei of the lymphocytes. The MUM1+ cells in reactive lymph nodes were found to consist of plasma cells and a small fraction (approximately 7.9%) of B cells harboring CD20+CD38+, which were located in the light zone of the germinal center. MUM1 expression in peripheral blood B/T lymphocytes was upregulated by mitogenic stimuli, suggesting that MUM1 positivity represents the activated state of the B/T cells. In B cell non-Hodgkin's lymphoma (NHL), MUM1 expression was observed in 73.2% (30/41) of diffuse large B cell lymphoma (DLBCL), 20% (1/5) of marginal zone lymphoma (MZL) and 43% (3/7) of small lymphocytic lymphoma (SLL) cases, whereas it was not seen in any cases of mantle cell lymphoma (MCL) or follicle center lymphoma (FCL). Also, MUM1 was stained at high intensity in various types of T cell lymphomas including adult T cell leukemia/lymphoma (ATL/L) and anaplastic large cell lymphoma (ALCL) and in the majority of Hodgkin's diseases. Our results suggest that a major proportion of lymphomas comprise either physiologically or aberrantly activated neoplastic lymphocytes expressing the MUM1 protein.
Asunto(s)
Proteínas de Unión al ADN/genética , Neoplasias Hematológicas/genética , Factores de Transcripción/genética , Translocación Genética , Linfocitos B/metabolismo , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 6/ultraestructura , Proteínas de Unión al ADN/biosíntesis , Elementos de Facilitación Genéticos , Regulación Neoplásica de la Expresión Génica , Centro Germinal/metabolismo , Centro Germinal/patología , Neoplasias Hematológicas/patología , Enfermedad de Hodgkin/genética , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Factores Reguladores del Interferón , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Activación de Linfocitos , Linfoma/clasificación , Linfoma/genética , Linfoma/metabolismo , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/patología , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Células Plasmáticas/metabolismo , Linfocitos T/metabolismo , Factores de Transcripción/biosíntesis , Transcripción GenéticaRESUMEN
This case describes the autopsy findings of a 2-month-old male infant with extensive and severe developmental brain abnormalities, including microcephaly, neocortical neuronal layering abnormalities, leptomeningeal heterotopias, commissural agenesis, and cerebellar and brainstem hypoplasia. Microarray analysis identified a gain in chromosome band 6q27, which includes the entire coding region of THBS2. THSB2 encodes thrombospondin 2 (TSP2), an astrocyte secreted protein of the extracellular matrix that promotes synaptogenesis, neurite outgrowth, and cerebellar granule cell migration. Thrombospondin 2 is not a matrix structural protein; instead it serves as an extracellular modulator of cell function, so it is considered a matricellular protein. The neuropathological findings at autopsy are compatible with perturbations in several known functions of TSP2 and demonstrate that TSP2 dysregulation can have a significant negative impact on human brain development. Furthermore, this case demonstrates the important role of astrocytes in human brain development.
Asunto(s)
Astrocitos/citología , Encéfalo/anomalías , Duplicación Cromosómica , Cromosomas Humanos Par 6/ultraestructura , Matriz Extracelular/metabolismo , Trombospondinas/genética , Autopsia , Axones/metabolismo , Encéfalo/embriología , Encéfalo/metabolismo , Movimiento Celular , Hibridación Genómica Comparativa , Femenino , Regulación de la Expresión Génica , Humanos , Recién Nacido , Masculino , Neuronas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Adulto JovenRESUMEN
BACKGROUND: The 6p21.3 region of human chromosome 6 is a genetic locus for schizophrenia, juvenile myoclonic epilepsy, and dyslexia. METHODS: Due to our interest in these disorders we performed complementary DNA (cDNA) hybridization selection on genomic DNA clones spanning this region to identify potential positional-candidate genes. RESULTS: We identified a full-length cDNA with an open reading frame of 2883 bp corresponding to a predicted protein of 961 amino acids that shares greater than 95% homology with the rat gamma-aminobutyric acid B (GABAB) receptor. Northern blot hybridization identified a 4.4-kb transcript in human brain. The human gene mapped to two sites on 6p21.3 separated by 2 Mb. Sequence analysis of both sites showed that the centromeric gene is transcribed, whereas the telomeric site is likely a pseudogene. The transcribed gene is distributed over 22 exons spanning 18 kb of genomic DNA. CONCLUSIONS: The genomic location, tissue expression, and function of the human GABAB receptor gene suggest that it is an important positional-candidate for the neurobehavioral disorders with a genetic locus on 6p21.3. In addition, delineation of the genomic organization will now permit it to be integrated as part of pharmacogenetic studies in trials of anxiolytic, narcotic, antiepileptic, and fluoxetine therapies.
Asunto(s)
Cromosomas Humanos Par 6/genética , Clonación Molecular/métodos , ADN Complementario/genética , Regulación de la Expresión Génica/fisiología , Receptores de GABA-B/genética , Northern Blotting , Mapeo Cromosómico , Cromosomas Humanos Par 6/ultraestructura , Cósmidos/genética , ADN Complementario/biosíntesis , Exones/genética , Regulación de la Expresión Génica/genética , Marcadores Genéticos , Genoma , Humanos , Intrones/genética , Hibridación de Ácido Nucleico , Sistemas de Lectura Abierta/genética , Levaduras/genéticaRESUMEN
We report a unique case of de novo acute promyelocytic leukemia (APL) with cryptic 15;17 rearrangements. Cytogenetically, structural rearrangements of the 6p23 region has been reported mainly in secondary leukemia. This patient had a karyotype of 46, XY, del(6)(p23) and no additional chromosomal abnormalities. Molecular analyses revealed the presence of PML-RAR alpha fusion genes. Deletion of the 6p23 region is extremely rare in APL.