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)
Anticonvulsivantes/uso terapéutico , Cromosomas Humanos Par 9/genética , Epilepsias Parciales/genética , Agonistas del GABA/uso terapéutico , Trastornos del Neurodesarrollo/genética , Receptores de GABA-B/deficiencia , Espasmos Infantiles/genética , Vigabatrin/uso terapéutico , Animales , Cromosomas Humanos Par 9/ultraestructura , Sustitución de Medicamentos , Electroencefalografía , Epilepsias Parciales/tratamiento farmacológico , Epilepsias Parciales/fisiopatología , Humanos , Lactante , Levetiracetam/uso terapéutico , Masculino , Modelos Animales , Destreza Motora , Trastornos del Neurodesarrollo/tratamiento farmacológico , Fenobarbital/uso terapéutico , Polimorfismo de Nucleótido Simple , Receptores de GABA-B/genética , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/fisiopatologíaRESUMEN
Chronic Myeloid Leukemia (CML) is myeloproliferative neoplasm characterized by Philadelphia chromosome which is a balanced translocation between chromosome 9 and 22 in 90% of cases. However, variant cytogenetic still happens in 5-10 % of cases, the importance of which is controversial as well as its response to therapy, prognosis and progression to acute leukemias. Here we report a male patient with CML and variant cytogenetic who responded to low dose of Dasatinib (50 mg daily).
Asunto(s)
Cariotipo Anormal , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Translocación Genética , Antineoplásicos/uso terapéutico , Médula Ósea/patología , Aberraciones Cromosómicas , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 17/ultraestructura , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 22/ultraestructura , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/ultraestructura , Dasatinib/uso terapéutico , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression. METHODS: We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study. RESULTS: We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved. CONCLUSION: These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.
Asunto(s)
Cromosomas Humanos Par 9/ultraestructura , Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Anciano , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Variación Genética , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Linfocitos/citología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Control de Calidad , ARN Mensajero/metabolismo , Análisis de Secuencia de ADNAsunto(s)
Crisis Blástica/genética , Cromosomas Humanos Par 12/ultraestructura , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Trastornos Mieloproliferativos/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Translocación Genética , Adulto , Médula Ósea/patología , Bandeo Cromosómico , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 9/genética , Errores Diagnósticos , Humanos , Hibridación Fluorescente in Situ , Ganglios Linfáticos/patología , Masculino , Trastornos Mieloproliferativos/clasificación , Trastornos Mieloproliferativos/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnósticoAsunto(s)
Cromosomas Humanos Par 8/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Proteínas de Fusión Oncogénica/fisiología , Translocación Genética , Adulto , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 9/genética , Eritropoyesis , Células Madre Hematopoyéticas/patología , Humanos , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Células Neoplásicas Circulantes , Células Madre Neoplásicas/patología , Proteínas de Fusión Oncogénica/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/análisis , Factor de Transcripción STAT5/análisisRESUMEN
OBJECTIVE: To assess the value of the study of chromosomal alterations by fluorescent in situ hybridization in a series of patients diagnosed of urothelial carcinoma and a minimum follow up of twenty four months, as well as evaluate its putative predictive potential. MATERIAL AND METHODS: The overall series includes 338 samples from 98 patients with 84 episodes of urothelial carcinoma. A subgroup of 24 patients who had at least one recurrence during the follow up was used to evaluate the predictive potential of the test. Three categories were considered (positive coherent episode, negative coherent episode, and incoherent episode) depending on the relationship between the fluorescent in situ hybridization result in the concomitant study of the new episode and those of the preceding samples. RESULTS: Fluorescent in situ hybridization showed higher sensitivity regardless of grade, negative predictive value and accuracy, while specificity and positive predictive value were superior with conventional cytology. In the recurrence, series 19/29 episodes were coherent, 11/19 were positive coherent with urothelial carcinoma all high grade and 8/19 negative coherent, most low grade. CONCLUSIONS: Fluorescent in situ hybridization test shows good sensitivity during a follow up of twenty four months and is able to predict recurrence, especially in cases of high grade. Our data demonstrate the existence of urothelial carcinomas without detectable chromosomal abnormalities by currently available methodology. The results support a multidisciplinary follow up combining fluorescent in situ hybridization, cytology and cystoscopy.
Asunto(s)
Carcinoma de Células Transicionales/genética , Aberraciones Cromosómicas , Hibridación Fluorescente in Situ , Recurrencia Local de Neoplasia/genética , Neoplasias de la Vejiga Urinaria/genética , Algoritmos , Aneuploidia , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/epidemiología , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/terapia , Cromosomas Humanos Par 17/ultraestructura , Cromosomas Humanos Par 3/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/ultraestructura , Cistoscopía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Clasificación del Tumor , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Prueba de Papanicolaou , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapia , Orina/citologíaRESUMEN
The translocation t(8;9)(p22;p24) is a rare event that results in the fusion of JAK2 to PCM1 and thus leads to the activation of the Janus Kinase 2. In 2008, the WHO introduced a new entity called "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1", which are characterized by the formation of a fusion gene encoding an aberrant tyrosine kinase. These disorders share characteristics with myeloproliferative neoplasms and typically show an eosinophilia. We here now report on 6 new cases with PCM1-JAK2 fusion. These patients show characteristics with respect to epidemiology, clinical presentation, and genetic changes that are very similar to patients with rearrangements of PDGFRA, PDGFRB, or FGFR1. Our data suggests the integration of cases with JAK2-PCM1 fusion in the respective WHO category of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1.
Asunto(s)
Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 9/genética , Eosinofilia/genética , Leucemia/clasificación , Trastornos Mieloproliferativos/clasificación , Proteínas de Fusión Oncogénica/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Translocación Genética/genética , Adulto , Anciano , Médula Ósea/patología , Niño , Cromosomas Humanos Par 8/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia/diagnóstico , Leucemia/genética , Leucemia/patología , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Leucemia Mieloide/patología , Linfocitos/patología , Masculino , Persona de Mediana Edad , Mutación , Células Mieloides/patología , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Organización Mundial de la SaludAsunto(s)
Cromosomas Humanos Par 9/ultraestructura , Eliminación de Gen , Genes p16 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Translocación Genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/administración & dosificación , Niño , Cromosomas Humanos Par 9/genética , Evolución Clonal , Células Clonales/ultraestructura , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib , Cariotipo , Masculino , Células Madre Neoplásicas/ultraestructura , Cromosoma Filadelfia , Piperazinas/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificaciónAsunto(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 & dosificaciónAsunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Deleción Cromosómica , Cromosomas Humanos Par 5/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Factores Inmunológicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Talidomida/análogos & derivados , Anciano , Médula Ósea/patología , Femenino , Humanos , Lenalidomida , Síndromes Mielodisplásicos/genética , Neoplasia Residual , Inducción de Remisión , Talidomida/uso terapéuticoRESUMEN
Chronic myelogenous leukemia (CML) is genetically characterized by the reciprocal translocation of chromosome 9 and 22. Around 5-8% of CML develop complex variant Ph translocations involving one or more chromosomal regions besides 9 and 22. Chromosome 3 is not frequently involved in complex translocations in CML. We report in this study a case of CML displaying a t(3;9;22) 3-way translocation. A review of the literature appears to indicate that CML patients with this translocation tend to have an aggressive course and poor outcome. Additional 3-way chromosome translocations associated with CML are also reviewed.
Asunto(s)
Cromosomas Humanos Par 22/ultraestructura , Cromosomas Humanos Par 3/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Leucemia Mieloide de Fase Crónica/genética , Translocación Genética , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas , Crisis Blástica/genética , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 9/genética , Ciclofosfamida/administración & dosificación , Dasatinib , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos , Resultado Fatal , Humanos , Mesilato de Imatinib , Cariotipificación , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/patología , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Cromosoma Filadelfia , Piperazinas/administración & dosificación , Piperazinas/farmacología , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Rituximab , Tiazoles/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
Gene Ontology (GO) provides a controlled vocabulary to describe the attributes of genes and gene products in any organism. Although one might initially wonder what relevance a 'controlled vocabulary' might have for cardiovascular science, such a resource is proving highly useful for researchers investigating complex cardiovascular disease phenotypes as well as those interpreting results from high-throughput methodologies. GO enables the current functional knowledge of individual genes to be used to annotate genomic or proteomic datasets. In this way, the GO data provides a very effective way of linking biological knowledge with the analysis of the large datasets of post-genomics research. Consequently, users of high-throughput methodologies such as expression arrays or proteomics will be the main beneficiaries of such annotation sets. However, as GO annotations increase in quality and quantity, groups using small-scale approaches will gradually begin to benefit too. For example, genome wide association scans for coronary heart disease are identifying novel genes, with previously unknown connections to cardiovascular processes, and the comprehensive annotation of these novel genes might provide clues to their cardiovascular link. At least 4000 genes, to date, have been implicated in cardiovascular processes and an initiative is underway to focus on annotating these genes for the benefit of the cardiovascular community. In this article we review the current uses of Gene Ontology annotation to highlight why Gene Ontology should be of interest to all those involved in cardiovascular research.
Asunto(s)
Enfermedades Cardiovasculares/clasificación , Enfermedades Cardiovasculares/genética , Biología Computacional/métodos , Enfermedades Cardiovasculares/diagnóstico , Cromosomas Humanos Par 9/ultraestructura , Bases de Datos Factuales , Bases de Datos de Proteínas , Genes , Genoma , Estudio de Asociación del Genoma Completo , Genómica/métodos , Humanos , Proteómica/métodos , Terminología como Asunto , Vocabulario ControladoRESUMEN
We evaluated the usefulness of interphase fluorescence in situ hybridization (FISH) for the detection of bone marrow involvement of lymphoma, comparing the results with those of microscopic examination. Bone marrow aspirates obtained for staging work-up from 150 patients with non-Hodgkin lymphoma were used in this study. Interphase FISH study using four probes and conventional G-banding were performed on bone marrow aspirates. The four probes included locus specific identifier (LSI) immunoglobulin heavy chain (IGH) dual-color break-apart rearrangement probe, an LSI p16 SpectrumOrange/CEP 9 SpectrumGreen probe, an LSI BCL6 dual-color break-apart rearrangement probe. Among 150 cases, 29 cases (19.3%) showed infiltration of neoplastic lymphoid cells by microscopic examination. Chromosomal aberrations were detected by FISH in eight patients and by conventional cytogenetic study in three patients. FISH study showed 14q32 rearrangement in four patients (4/126, 3.2%), 9q21 rearrangement in no patients (0/144, 0%), 3q27 rearrangement in four patients (4/131. 3.1%), and a gain of 1q21q32 in two patients (2/115, 1.7%). Among eight patients with abnormal FISH patterns, six had normal karyotypes or no analyzable metaphase according to the conventional cytogenetic study. Seven patients with FISH abnormality showed bone marrow involvement of lymphoma by microscopic examination. One patient, who was defined as having no evidence of bone marrow involvement by microscopic examination, showed a 3q27 aberration in the FISH study. Although the number of patients with BM involvement that was detected by FISH was low, abnormal FISH patterns were detected in six patients who did not have abnormal karyotypes. Therefore, FISH analysis would be beneficial in cytogenetic diagnosis and follow-up study of minimal residual diseases, once the cytogenetic changes are detected at initial diagnosis.
Asunto(s)
Examen de la Médula Ósea/métodos , Médula Ósea/patología , Hibridación Fluorescente in Situ , Linfoma no Hodgkin/patología , Estadificación de Neoplasias/métodos , Adulto , Anciano , Aberraciones Cromosómicas , Bandeo Cromosómico , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 1/ultraestructura , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 3/ultraestructura , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/ultraestructura , Femenino , Humanos , Interfase , Cariotipificación , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/genética , Masculino , Persona de Mediana EdadRESUMEN
We studied JAK2 mutational status, in combination with cytogenetic analysis in 54 patients with essential thrombocythemia (ET), and attempted to obtain greater insight into the correlation between clinicohematologic features and genetic abnormalities. We found that six ET patients developed myelofibrosis and four of them had JAK2 V617F mutation. It is noteworthy that three of the four ET patients with JAK2 V617F had add(18)(p11). In contrast, the remaining two ET patients who developed myelofibrosis had neither JAK2 V617F nor add(18)(p11). Moreover, none of the ET patients with JAK2 V617F and chromosome changes other than add(18)(p11) developed myelofibrosis. The current results indicate that add(18)(p11), possibly due to der(9;18), may contribute a link to myelofibrosis in JAK2 V617F-positive ET patients, while those with wild-type JAK2 may use another pathway toward myelofibrosis.
Asunto(s)
Sustitución de Aminoácidos , Cromosomas Humanos Par 18/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Janus Quinasa 2/genética , Mutación Missense , Mutación Puntual , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Adulto , Anciano , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 9/genética , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide/etiología , Leucemia Mieloide/genética , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/etiología , Mielofibrosis Primaria/patología , Cariotipificación Espectral , Trombocitemia Esencial/patologíaAsunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Metotrexato/farmacocinética , Piperazinas/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Pirimidinas/farmacología , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/análisis , Benzamidas , Cromosomas Humanos Par 22/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Citarabina/administración & dosificación , Interacciones Farmacológicas , Edema/inducido químicamente , Edema/tratamiento farmacológico , Etopósido/administración & dosificación , Femenino , Humanos , Mesilato de Imatinib , Leucovorina/uso terapéutico , Metotrexato/administración & dosificación , Metotrexato/análisis , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Derrame Pleural Maligno/inducido químicamente , Derrame Pleural Maligno/química , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/uso terapéutico , Translocación GenéticaRESUMEN
Chromosomal translocations joining the immunoglobulin (IG) and MYC genes have been extensively reported in Burkitt's and non-Burkitt's lymphomas but data concerning MYC rearrangements with non-IG partners are scarce. In this study, 8q24 breakpoints from 17 B-cell lymphomas involving non-IG loci were mapped by fluorescence in situ hybridization (FISH). In seven cases the breakpoint was inside a small region encompassing MYC: in one t(7;8)(p12;q24) and two t(3;8)(q27;q24), it was telomeric to MYC whereas in four cases, one t(2;8)(p15;q24) and three t(8;9)(q24;p13) it was located in a 85 kb region encompassing MYC. In these seven cases, partner regions identified by FISH contained genes known to be involved in lymphomagenesis, namely BCL6, BCL11A, PAX5 and IKAROS. Breakpoints were cloned in two t(8;9)(q24;p13), 2.5 and 7 kb downstream from MYC and several hundred kb 5' to PAX5 on chromosome 9, joining MYC to ZCCHC7 and to ZBTB5 exon 2, two genes encoding zinc-finger proteins. In these seven cases, MYC expression measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) was significantly higher when compared to that of patients without 8q24 rearrangement (P=0.006). These results suggest that these rearrangements are the consequence of a non-random process targeting MYC together with non-IG genes involved in lymphocyte differentiation and lymphoma progression.
Asunto(s)
Rotura Cromosómica , Cromosomas Humanos Par 8/genética , Genes myc , Linfoma de Células B/genética , Translocación Genética/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Linfoma de Burkitt/genética , Proteínas Portadoras/genética , Transformación Celular Neoplásica/genética , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 2/ultraestructura , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 3/ultraestructura , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 7/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/ultraestructura , Proteínas de Unión al ADN/genética , Femenino , Humanos , Factor de Transcripción Ikaros/genética , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Factor de Transcripción PAX5/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Proteínas Represoras , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
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
Four of 9 PAX transcription factor genes have been associated with chromosomal translocations in human tumors, although their oncogenic potential has not yet been demonstrated in transgenic mouse models. The B-lymphoidPAX5 gene participates in the generation of the t(9;14)(p13;q32) translocation in germinal center B cells, which leads to deregulated PAX5 expression under the control of the immunoglobulin heavy-chain (IgH) locus in a subset of B-cell non-Hodgkin lymphomas. Here we reconstructed a human t(9;14) translocation in a knock-in mouse by inserting a PAX5 minigene into the IgH locus. The IgH(P5ki) allele, which corresponds to a germline rather than somatic mutation, is activated in multipotent hematopoietic progenitors and is subsequently expressed in dendritic cells (DCs) and in natural killer (NK), T, and B cells. Ectopic Pax5 expression interferes with normal T-cell development and causes immature T-lymphoblastic lymphomas in IgH(P5ki/+) and IgH(P5ki/P5ki) mice. Aggressive T-cell lymphomas develop even faster in Ik(Pax5/+) mice expressing Pax5 from the Ikaros locus. Pax5 expression in thymocytes activates B-cell-specific genes and represses T-lymphoid genes, suggesting that Pax5 contributes to lymphomagenesis by deregulating the T-cell gene-expression program. These data identify Pax5 as a potent oncogene and demonstrate that the T-lymphoid lineage is particularly sensitive to the oncogenic action of Pax5.
Asunto(s)
Diferenciación Celular/genética , Transformación Celular Neoplásica/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 9/genética , Cadenas Pesadas de Inmunoglobulina/genética , Células Madre Neoplásicas/patología , Factor de Transcripción PAX5/fisiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Regiones Promotoras Genéticas , Linfocitos T/patología , Translocación Genética , Alelos , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Trasplante de Médula Ósea , Linaje de la Célula , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Células Dendríticas/metabolismo , Células Dendríticas/patología , Células Madre de Carcinoma Embrionario , Regulación Neoplásica de la Expresión Génica , Humanos , Factor de Transcripción Ikaros/genética , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Linfocitos/metabolismo , Linfocitos/patología , Linfoma de Células B/genética , Linfoma de Células B/patología , Ratones , Ratones Endogámicos C57BL , Mutagénesis Insercional , Trasplante de Neoplasias , Células Madre Neoplásicas/metabolismo , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Quimera por Radiación , Linfocitos T/metabolismoRESUMEN
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder characterized by a proliferation mainly of mature neutrophils. The prognosis is generally poor and an optimal therapeutic strategy remains to be determined. Allogeneic hematopoietic stem cell transplantation (HSCT) is expected to be the only curative therapy so far. We report a 46-year-old male with progressive CNL who underwent bone marrow transplantation from an HLA-matched unrelated donor. After engraftment was achieved on day 35, relapse of CNL was confirmed on day 50. The progression of CNL was very rapid afterward and infiltration to the central nervous system was observed. The Janus Kinase 2 (JAK2) V617F homozygous mutation was detected from the peripheral blood or bone marrow samples throughout the clinical course. From comparison with reports of successful HSCT for CNL in the literature, it was inferred that HSCT should be performed in a stable status before progression. Furthermore, JAK2 V617F-positive CNL may contain an aggressive disease entity in contrast to previous reports. Accumulation of experiences is required to establish a definite role of HSCT in the treatment of CNL and a prognostic significance of JAK2 mutation in CNL.