Genomic instability in a chronic lymphocytic leukemia patient with mono-allelic deletion of the DLEU and RB1 genes.

BACKGROUND: The most frequent cytogenetic abnormality detected in chronic lymphocytic leukemia (CLL) patients is the presence of a deletion within the chromosome band 13q14. Deletions can be heterogeneous in size, generally encompassing the DLEU1 and DLEU2 genes (minimal deleted region), but at times also including the RB1 gene. The latter, larger type of deletions are associated with worse prognosis.Genomic instability is a characteristic of most cancers and it has been observed in CLL patients mainly associated with telomere shortening. CASE PRESENTATION: Cytogenetic and fluorescence in situ hybridization studies of a CLL patient showed a chromosomal translocation t(12;13)(q15;q14), a mono-allelic 13q14 deletion encompassing both the DLEU and RB1 genes, and genomic instability manifested as chromosomal breaks, telomeric associations, binucleated cells, nucleoplasmic bridges, and micronucleated cells.In conclusion, our CLL patient showed genomic instability in conjunction with a 13q14 deletion of approximately 2.6 megabase pair involving the DLEU and RB1 genes, as well as other genes with potential for producing genomic instability due to haploinsufficiency.

[Cytogenetics of myelodysplastic syndromes and its impact as prognostic factor]. / La citogenética de los síndromes mielodisplásicos y su impacto como factor pronóstico.

Myelodysplastic syndromes (MDS) are a group of disorders of the hematopoietic stem cell. They are characterized by cytopenia(s), dysplasia of one or more cell lines, ineffective hematopoiesis, and an increased risk for developing acute myelogenous leukemia. The classification of MDS has been complicated due to the great heterogeneity in clinical phenotype as well as in the morphological and cytogenetic characteristics. The prognostic value of cytogenetic abnormalities in MDS has been analyzed in multicenter studies. This approach raised the development of the revised International Prognostic Scoring System (IPSS-R), which analyzes five prognostic variables, among which the cytogenetic study stands out. According to the cytogenetic findings, a classification of MDS in five subgroups was developed. Knowledge of the cytogenetic abnormalities has led to the study of genes involved in various chromosomal rearrangements. Moreover, DNA sequencing has helped to identify mutations in approximately 50 genes related to signal transduction, DNA methylation, transcriptional regulation, and RNA splicing. Therefore, the cytogenetic study should be used to improve the classification and therapeutic management of MDS. This approach will be an essential tool for the development of targeted therapy protocols.

Los síndromes mielodisplásicos (SMD) son un grupo de alteraciones que involucran a las células madre hematopoyéticas, caracterizadas por citopenia(s), displasia en una o más líneas celulares, hematopoyesis ineficaz y riesgo mayor para desarrollar leucemia aguda mieloblástica. Su clasificación es complicada debido a la heterogeneidad citogenética que condiciona un fenotipo morfológico y clínico también variable. El valor pronóstico de las alteraciones citogenéticas ha sido analizado en estudios multicéntricos y culminó con el desarrollo del Sistema Internacional Revisado de Puntaje Pronóstico (IPSS-R), que analiza cinco variables pronósticas, entre las que destaca el estudio citogenético. Este estudio ha identificado cinco categorías con valor pronóstico: muy bueno, bueno, intermedio, malo y muy malo. El conocimiento de tales alteraciones ha conducido al estudio de genes involucrados en los distintos arreglos cromosómicos, habiendo identificado mutaciones en cerca de 50 genes, mismos que están relacionados con la transducción de señales, la metilación del ácido desoxirribonucleico (ADN), la regulación de la transcripción y con el proceso de corte y empalme del ARN. Actualmente el estudio citogenético es el estándar de oro para el correcto estudio y clasificación de los SMD.

1,2:3,4-Diepoxybutane Induces Multipolar Mitosis in Cultured Human Lymphocytes.

1,3-Butadiene, a colorless gas regularly used in the production of plastics, thermoplastic resins, and styrene-butadiene rubber, poses an increased leukemia mortality risk to workers in this field. 1,3-Butadiene is also produced by incomplete combustion of motor fuels or by tobacco smoking. It is absorbed principally through the respiratory system and metabolized by several enzymes rendering 1,2:3,4-diepoxybutane (DEB), which has the highest genotoxic potency of all metabolites of 1,3-butadiene. DEB is considered a carcinogen mainly due to its high potential as clastogen, which induces structural chromosome aberrations such as sister chromatid exchanges, chromosomal breaks, and micronuclei. Due to its clastogenic effect, DEB is one of the most used agents for diagnostic studies of Fanconi anemia, a recessively inherited disease related to mutations affecting several genes involved in a common DNA repair pathway. When performing Fanconi anemia diagnostic tests in our laboratory, we have observed occasional multipolar mitosis (MM) in lymphocyte cultures exposed to 0.1 µg/ml of DEB and harvested in the absence of any mitotic spindle inhibitor. Although previous studies reported an aneugenic effect (i.e. it induces aneuploidy) of DEB, no mechanism was suggested to explain such observations. Therefore, the aim of this study was to investigate whether exposure to 0.1 µg/ml of DEB is significantly associated with the occurrence of MM. We blindly assessed the frequency of MM in lymphocyte cultures from 10 nonsmoking healthy individuals. Two series of 3 cultures were performed from each sample under different conditions: A, without DEB; B, with 0.1 µg/ml of DEB, and C, with 25 µM of mitomycin C as positive control. Cultures exposed to DEB showed higher frequencies of MM (23 of 2,000 cells) than did the unexposed ones (3 of 2,000 cells).