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Introducción: La leucemia linfoide aguda es una proliferación y transformación maligna de las células progenitoras linfoides en la médula ósea, la sangre y los sitios extramedulares. Es la neoplasia más frecuente en la infancia. Constituye el 80 % de todas las leucemias agudas de la edad pediátrica y la más frecuente de las que se originan a partir del linaje de células B. Desde el punto de vista genético se presentan múltiples alteraciones moleculares y cromosómicas que son utilizadas para la estratificación pronóstica. Objetivo: Describir los biomarcadores genéticos de la leucemia linfoide aguda de linaje B y su implicación pronóstica. Métodos: Se realizó una revisión de la literatura en los idiomas inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico, de artículos publicados en los últimos cinco años. Se efectuaron un análisis y resumen de la bibliografía revisada. Conclusiones: En la leucemia linfoide aguda de linaje B se detectan múltiples alteraciones citogenéticas como las traslocaciones t(9;22) y la t(12;21), rearreglos en 11q23 que generan genes de fusión, así como otras aberraciones cromosómicas y mutaciones génicas. Este espectro genético involucra genes que participan en el desarrollo de las células linfoides y en la regulación del ciclo celular. El conocimiento de su biología, a partir del estudio de las alteraciones genéticas como biomarcadores predictivos, permite la estratificación de la leucemia linfoide aguda y la aplicación de tratamientos más personalizados para evitar recaídas.
Introduction: Acute lymphoid leukemia is a proliferation and malignant transformation of lymphoid progenitor cells in the bone marrow, blood and extramedullary sites. It is the most common neoplasm in childhood; it constitutes 80% of all acute leukemias in children; and the most frequent of those that originate from the B cell lineage. From the genetic point of view, there are multiple molecular and chromosomal alterations. Objective: To describe the genetic biomarkers of the disease and its prognostic implication. Methods: A review of the literature in English and in Spanish was carried out, in the PubMed website and using the search engine of Google Scholar, for articles published in the last five years. We performed analysis and summary of the reviewed bibliography. Conclusions: In acute lymphoid leukemia, multiple cytogenetic alterations are detected, such as translocation t(9;22), t(12;21), rearrangements in 11q23 that generate fusions genes as well as other chromosomal aberrations and gene mutation. This genetic spectrum involves genes that participate in the development of lymphoid cells and in the regulation of the cell cycle. Knowledge of its biology, based on the study of genetic alterations as predictive biomarkers, allows the stratification of Acute lymphoid leukemia and the application of more personalized treatments to avoid relapses.
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La Leucemia Linfoblástica Aguda (LLA) es la neoplasia más frecuente en edad pediátrica. En los últimos años, entre el 15 y 20% de los pacientes fracasan en el tratamiento. Conocimientos en citogenética y biología molecular repercuten de manera importante en la determinación del pronóstico y del esquema de tratamiento adecuado. En Venezuela existe un conocimiento limitado en cuanto a la genética molecular de esta alteración onco-hematológica. El objetivo del trabajo fue evaluar las alteraciones genéticas más frecuentes en pacientes venezolanos con diagnóstico clínico de leucemia linfoblástica aguda. Se realizó un estudio transversal, descriptivo y prospectivo de 2006 a 2014, en el que se evaluaron las translocaciones ETV6/RUNX1, MLL/AF4, TCF3/PBX1, BCR/ABL1, así como las mutaciones en los genes PAX5 y FLT3 mediante el uso de diferentes tipos de PCR. Ciento treinta pacientes con diagnóstico clínico de leucemia linfocítica aguda fueron incluidos en el estudio. Se identificaron alteraciones moleculares en 56 pacientes (43,1%), en los que observamos la presencia de una o varias alteraciones en conjunción en un mismo paciente. Las alteraciones identificadas fueron t(12;21) (11,5%), t(4;11) (8,5%), t(1;19) (10%), t(9;22) (20,8%), ITD-FLT3 (14,8%), mutación P80S (4,2%) y S77del (4,2%) en el gen PAX5. La prevalencia de BCR/ ABL, es una de las más altas que ha sido descrita hasta ahora en casos de LLA donde la mayor parte de la población está conformada por pacientes pediátricos. Estos resultados representan el primer estudio molecular de la LLA en Venezuela, sentando las bases para el diagnóstico y seguimiento de la enfermedad en su población.
Acute Lymphoblastic Leukemia (ALL) is the most common neoplasm in pediatric age. In recent years, between 15 and 20% of patients failed in their treatments. Knowledge on cytogenetics and molecular biology has an important impact on the determination of the prognosis and the appropriate treatment scheme. In Venezuela there is limited knowledge regarding the molecular genetics of this onco-hematological alteration. The aim of this work was to evaluate the most frequent genetic alterations in Venezuelan patients with a clinical diagnosis of acute lymphoblastic leukemia. A cross-sectional, descriptive and prospective study was carried out from 2006 to 2014, in which the translocations ETV6/RUNX1, MLL/AF4, TCF3/PBX1, BCR/ABL1, as well as mutations in the PAX5 and FLT3 genes were evaluated through the use of different types of PCR. One hundred and thirty patients with a clinical diagnosis of acute lymphocytic leukemia were included in the study. Molecular alterations were identified in 56 patients (43.1%), in which we observed the presence of one or several alterations in conjunction in the same patient. The alterations identified were t(12; 21) (11.5%), t(4; 11) (8.5%), t(1; 19) (10%), t(9; 22) (20.8%), ITD-FLT3 (14.8%), P80S mutation (4.2%) and S77del (4.2%) in the PAX5 gene. The prevalence of BCR/ABL is one of the highest described so far in cases of ALL where most of the population is made up of pediatric patients. These results represent the first molecular study of ALL in Venezuela, laying the foundations for the diagnosis and monitoring of the disease in its population.
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Over the last couple of decades, with the crisis of new antimicrobial arsenal, multidrug-resistant clinicalpathogens have been observed extensively. In clinical and medical settings, these persistent pathogens predominantly grow as complex heterogeneous structures enmeshed in a self-produced exopolysaccharide matrix,termed as biofilms. Since biofilms can rapidly form by adapting new environmental surroundings and havepotential effect on human health, it is critical to study them promptly and consistently. Biofilm infections arechallenging in the contamination of medical devices and implantations, food processing and pharmaceuticalindustrial settings, and in dental area caries, periodontitis and so on. The persistence of infections associatedwith biofilms has been mainly attributed to the increased antibiotic resistance offered by the cells growing inbiofilms. In fact, it is well known that this recalcitrance of bacterial biofilms is multifactorial, and there areseveral resistance mechanisms that may act in parallel in order to provide an enhanced level of resistance to thebiofilm. In combination, distinct resistance mechanisms significantly decrease our ability to control anderadicate biofilm-associated infections with current antimicrobial arsenal. In addition, various factors areknown to influence the process of biofilm formation, growth dynamics, and their heterogeneous responsetowards antibiotic therapy. The current review discusses the contribution of cellular and physiochemical factorson the growth dynamics of biofilm, especially their role in antibiotic resistance mechanisms of bacterialpopulation living in surface attached growth mode. A systematic investigation on the effects and treatment ofbiofilms may pave the way for novel therapeutic strategies to prevent and treat biofilms in healthcare andindustrial settings.
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@#Myeloid sarcoma, characterized by the presence of immature myeloid cells occurring at an extramedullary site, is a rare manifestation of acute myelogenous leukemia (AML). Spinal cord compression as an initial presentation of AML is very rare with only a few reported cases. We discuss a case of a 22-year-old male who presented with bicytopenia and paraplegia. Workups were consistent with AML with monocytic differentiation. Chromosomal analysis revealed loss of Y and t (8;21). Spinal cord MRI showed intradural extramedullary-enhancing soft tissue lesions at levels T2 to T7 and L5 to S1, suspected to be myeloid sarcoma. Patient, however, succumbed to severe nosocomial infection prior to initiation of chemotherapy and radiotherapy.
Subject(s)
Humans , Leukemia, Monocytic, Acute , Sarcoma, Myeloid , Spinal Cord NeoplasmsABSTRACT
Translin, a highly conserved, DNA/RNA binding protein, is abundantly expressed in brain, testis and in certain malignancies. It was discovered initially in the quest to find proteins that bind to alternating polypurines-polypyrimidines repeats.It has been implicated to have a role in RNA metabolism (tRNA processing, RNAi, RNA transport, etc.), transcription,DNA damage response, etc. Studies from human, mice, drosophila and yeast have revealed that it forms an octameric ring,which is important for its function. Translin is a cytoplasmic protein, but under genotoxic stress, it migrates into thenucleus, binds to the break point hot spots and therefore, thought to be involved in chromosomal translocation events aswell as DNA damage related response. Its structure is known and DNA binding regions, GTP binding region and regionsresponsible for homotypic and heterotypic interaction are known. It forms a ball like structure with open central channel foraccommodating the substrate nucleic acids. Besides this, translin protein binds to 30 and 50 UTR of certain mRNAs andprobably regulates their availability for translation. It is also involved in mRNA transport and cell cycle progression. Itforms a heteromeric complex with translin associated factor-X (TRAX) to form C3PO complex which is involved in RNAsilencing process. Recently, it has been shown that translin is upregulated under starvation conditions in Drosophila and isinvolved in the integration of sleep and metabolic rate of the flies. Earlier studies classified translin as a DNA repair protein;however subsequent studies showed that it is a multifunctional protein. With this background, in this review we havesummarized the translin biochemical activities, cellular function as well as structural properties of this important protein.
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Precursor B-cell acute lymphoblastic leukemia (ALL), which is the most common subtype of pediatric acute leukemia, generally has a good prognosis. However, the prognosis also depends on the genetic abnormalities of the leukemic blast. Concurrent MYC and IGH/BCL2 translocations have recently been reported as a “double hit” in adult patients, but non-immunoglobulin (non-IG)/MYC translocation has rarely been reported. In this paper, we report a case of pediatric precursor B-cell ALL associated with translocations (14;18)(q32;q21) and (8;9)(q24;p13). The patient was a previously healthy 13-year-old boy. Complete remission was not achieved after first-line four-drug induction chemotherapy; thus, intensive salvage regimen, including high-dose cytarabine and L-asparaginase, were administered, which resulted in morphologic remission. However, his disease relapsed during the second cycle of salvage regimen, and he died of sepsis-induced multiorgan failure.
Subject(s)
Adolescent , Adult , Humans , Male , Cytarabine , Induction Chemotherapy , Leukemia , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cells, B-Lymphoid , PrognosisABSTRACT
Precursor B-cell acute lymphoblastic leukemia (ALL), which is the most common subtype of pediatric acute leukemia, generally has a good prognosis. However, the prognosis also depends on the genetic abnormalities of the leukemic blast. Concurrent MYC and IGH/BCL2 translocations have recently been reported as a “double hit” in adult patients, but non-immunoglobulin (non-IG)/MYC translocation has rarely been reported. In this paper, we report a case of pediatric precursor B-cell ALL associated with translocations (14;18)(q32;q21) and (8;9)(q24;p13). The patient was a previously healthy 13-year-old boy. Complete remission was not achieved after first-line four-drug induction chemotherapy; thus, intensive salvage regimen, including high-dose cytarabine and L-asparaginase, were administered, which resulted in morphologic remission. However, his disease relapsed during the second cycle of salvage regimen, and he died of sepsis-induced multiorgan failure.
Subject(s)
Adolescent , Adult , Humans , Male , Cytarabine , Induction Chemotherapy , Leukemia , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cells, B-Lymphoid , PrognosisABSTRACT
Objective To explore the distribution of prenatal indications , clinical features and pregnant outcomes of chromosomal unbalanced reciprocal translocations atthe second trimester. Methods The data on 35 fetuses with unbalanced reciprocal translocations between May 2011 and March 2016 were retrospectively analyzed and reviewed. Results Of 35 fetuses with unbalanced translocations , 29 (82.86%) showed ultrasound abnormalities,and 6 (17.14%) had no significant clinical features. 8 were de novo, and the other 27 were parental inherited. All the 35 women had to terminate the pregnancy. Conclusions Ultrasound abnormalities are associated with chromosomal unbalanced reciprocal translocations at the second trimester , and most unbalanced translocations fetuses origin from parental carrier of balanced translocations.
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B cell ALL is a subtype of Acute lymphoblastic leukemia (ALL). Till date, 3 dicentric’s: dic (7;9), dic(9;12) and dic(9;20) with t(9;22) were reported in B- ALL . The hematological profile revealed a white blood cell count of 324.3 X10³/mm3 with 74% blasts, a hemoglobin level of 6.2 g/dl and a platelet count of 50X109 /mm. Trephine biopsy revealed proliferations of blasts which are medium sized to large and had vesicular nuclei with indented nucleoli. The biochemical parameters were normal except elevated liver AST (67U/L);ALT(121U/L);GGTP(159U/L), alkaline phosphatase (251U/L) profiles and renal urea (46mg/dl),Creatinine (1.446mg/dl) and sodium (135mEq/L). The patient was positive for the Immunophenotypic markers CD10/CD19/CD34/ CD33 by Flowcytometry. Diagnosis of B- ALL was made. To our knowledge this dic(1;15)(p11:p11) with t(9;22) (q34;q11) is the first kind of report in B-ALL. Further molecular studies are required to elucidate the pathogenesis and prognostic significance of dic(1;15) in leukemia.
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Cytogenetics study using combination of conventional cytogenetics and fluorescent insitu hybridization was carried out in 171 pediatric acute lymphoblastic leukemia patients subgrouped to B-ALL (n=126) and T-ALL (n=45) by bone marrow morphology and immunophenotype. The chromosomal aberration frequency in B-ALL and T-ALL was 79% and 71%, respectively. TEL/AML1 translocation was detected in 28% of patients.
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BACKGROUND: Recurrent pregnancy loss is a common occurrence and a matter of concern for couples planning the pregnancy. Chromosomal abnormalities, mainly balanced rearrangements, are common in couples with repeated miscarriages. PURPOSE: The purpose of this study is to evaluate the contribution of chromosomal anomalies causing repeated spontaneous miscarriages and provide detailed characterization of a few structurally altered chromosomes. MATERIALS AND METHODS: A retrospective cytogenetic study was carried out on 4859 individuals having a history of recurrent miscarriages. The cases were analyzed using G‑banding and fluorescence in situ hybridization wherever necessary. RESULTS: Chromosomal rearrangements were found in 170 individuals (3.5%). Translocations were seen in 72 (42.35%) cases. Of these, reciprocal translocations constituted 42 (24.70%) cases while Robertsonian translocations were detected in 30 (17.64%) cases. 7 (4.11%) cases were mosaic, 8 (4.70%) had small supernumerary marker chromosomes and 1 (0.6%) had an interstitial microdeletion. Nearly, 78 (1.61%) cases with heteromorphic variants were seen of which inversion of Y chromosome (57.70%) and chromosome 9 pericentromeric variants (32.05%) were predominantly involved. CONCLUSIONS: Chromosomal analysis is an important etiological investigation in couples with repeated miscarriages. Characterization of variants/marker chromosome enable calculation of a more precise recurrent risk in a subsequent pregnancy thereby facilitating genetic counseling and deciding further reproductive options.
Subject(s)
Abortion, Spontaneous/epidemiology , Adolescent , Adult , Chromosome Aberrations/epidemiology , Female , Fetal Death/epidemiology , Genetic Linkage , Genetic Markers , India , Male , Middle Aged , Retrospective Studies , Translocation, Genetic , Young AdultABSTRACT
The presence of derivative chromosome in a child with phenotypic features necessitates the need of parental karyotyping to ascertain the exact amount of loss or gain of the genetic material. The aim of this study was to emphasize the importance of parental karyotyping. Cytogenetic evaluation of the proband and his father were carried out at Laboratory. Cytogenetic analysis was performed on phytohemagglutinin stimulated cultures. The derivative chromosome 11 in proband was ascertained to have additional material from chromosome 6p arising from complex chromosomal rearrangement in the father. Karyotyping is the basic, cost-effective preliminary investigation in a child with mental subnormality or congenital anomalies.
Subject(s)
Adult , Child, Preschool , Chromosomes, Human, Pair 3/genetics , Chromosomes, Human, Pair 6/genetics , Chromosomes, Human, Pair 11/genetics , Genetic Counseling , Humans , Intellectual Disability/diagnosis , Intellectual Disability/epidemiology , Intellectual Disability/genetics , /methods , Male , Translocation, GeneticABSTRACT
Multiplex reverse transcription polymerase chain reaction (mRT-PCR) has recently emerged as an alternative to cytogenetics. We designed and used simplified mRT-PCR system as a molecular screen for acute leukemia. Fifteen fusion transcripts were included: BCR-ABL1, PML-RARA, ZBTB16-RARA, RUNX1-RUNX1T1, CBFB-MYH11, DEK-NUP214, TCF3-PBX1, ETV6-RUNX1, MLL-AFF1, MLL-MLLT4, MLL-MLLT3, MLL-MLLT10, MLL-ELL, MLL-MLLT1, and MLL-MLLT6. A total of 121 diagnostic acute leukemia specimens were studied, comparing the mRT-PCR system with standard cytogenetics. Fifty-six cases (46.3%) had fusion transcripts revealed by our mRT-PCR assay. The concordance rate between mRT-PCR and cytogenetics was 91.7%. However, false negative results were found in three cases who have inv(16), t(4;11) or t(11;19)(q23;p13.1), respectively. Seven cryptic translocations including ETV6-RUNX1, MLL-MLLT3, MLL-MLLT4, and PML-RARA were detected. This mRT-PCR assay is a useful screening tool in acute leukemia because it provides rapid and reliable detection of clinically important chimeric transcripts. In addition, cryptic translocations provide additional genetic information that could be clinically useful.
Subject(s)
Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Young Adult , Acute Disease , Chromosome Inversion , Cytogenetics , Leukemia/diagnosis , Multiplex Polymerase Chain Reaction , Oncogene Proteins, Fusion/genetics , Prognosis , Translocation, GeneticABSTRACT
Los linfomas no Hodgkin de células T, son enfermedades malignas poco comunes. La clasificación actual WHO/EORTC, reconoce 10 entidades clínico patológicas diferentes, estas entidades tiene una única característica y requieren individualizar el diagnóstico y el tratamiento de los mismos. En años recientes se han hecho grandes progresos en el conocimiento de la patogenia de estas enfermedades. La traslocación cromosomal especifica, y las infecciones virales son asociadas actualmente a ciertos linfomas. En esta revisión se describen la presentación clínico patológica, y además se discuten los estudios moleculares en diagnóstico de de los linfomas de células T, debido a la rareza de estas entidades y la escasez de investigaciones a gran escala acerca de las mismas su tratamiento aun es un reto, basado en bases anecdóticas, requiriéndose aun estudios mas extensos acerca de las bases biológicas de estas enfermedades para poder obtener terapias mas satisfactorias.
T-cell non-Hodgkins lymphomas (NHLs) are uncommon malignancies. The current classification WHO/EORTC recognizes 10 different clinic pathologic entities. These disorders have unique characteristics and require individualized diagnostic and therapeutic strategies. Tremendous progress has been made in recent years in the understanding of the pathogenesis of these disorders. Specific chromosomal translocations and viral infections are now known to be associated with certain lymphomas. In this review, we describe their clinical and pathologic features. We also discuss the use of molecular studies in the diagnostic work-up of T-cell lymphomas. Because of the rarity of these disorders and the lack of well-designed clinical trials, the treatment of peripheral T-cell NHLs is often challenging. Additional studies are required to learn more about the biology of these diseases, which may lead to more optimal and possibly targeted therapies.
Subject(s)
Humans , Lymph Nodes , Lymphoid Tissue , Lymphoma, Non-Hodgkin , T-Lymphocytes , Translocation, GeneticABSTRACT
Topoisomerase II inhibitors are effective chemotherapeutic agents in the treatment of cancer, in spite of being associated with the development of secondary leukemia. Our purpose was to determine the effects of etoposide on different genomic regions, aiming at discovering whether there are preferential sites which can be targeted by this drug in peripheral lymphocytes from healthy individuals. The in vitro treatment with low doses of etoposide (0.25, 0.5, and 1 µg/mL, in 1 hour-pulse or continuous-48 h treatment) induced a significant increase in chromosomal aberrations, detected by conventional staining and FISH with specific probes for chromosomes 8 and 11, compared with untreated controls (p < 0.05). Additionally, the frequencies of alterations at 11q23, detected by MLL specific probes, were significantly higher (p < 0.005) in treated cells than in controls. In contrast, an analysis of rearrangements involving the IGH gene did not disclose differences between treatments. The present results demonstrated the potential of etoposide to interact with preferential chromosome sites in human lymphocytes, even at concentrations below the mean plasma levels measured in cancer patients. This greater susceptibility to etoposide-induced cleavage may explain the more frequent involvement of MLL in treatment-related leukemia.
Subject(s)
Humans , Adult , Etoposide , Leukemia/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Chromosome Aberrations , Cytogenetic Analysis , DNA Topoisomerases, Type II , In Situ Hybridization, Fluorescence , Neoplasms/drug therapy , Translocation, GeneticABSTRACT
La leucemia linfocítica aguda (LLA) representa aproximadamente el 80 % dentro de las leucemias pediátricas. Recientemente se ha demostrado por biología molecular la existencia de una translocación críptica, la t (12;21) (p12;q22) en la LLA de tipo B, que no se detecta por las técnicas citogenéticas convencionales e involucra los oncogenes TEL y AML1. Esta alteración es actualmente la más común en esta leucemia y se observa aproximadamente en el 25 % de los casos. Diversos investigadores han planteado que dicha translocación identifica a un subgrupo de pacientes con una evolución muy favorable, por lo que se considera un indicador de buen pronóstico. La determinación de la t (12;21) en el estudio de LLA tiene importancia pronóstica, además de servir como marcador para la detección de la enfermedad mínima residual. En nuestro trabajo estandarizamos la técnica de RT-PCR para la detección de la t (12;21) y además analizamos muestras de 20 pacientes pediátricos con LLA tipo B, que en el momento del estudio se encontraban en la fase de diagnóstico inicial o en recaída. En el estudio, 5 de los 20 pacientes mostraron reordenados los genes TEL/AML 1, lo que representa el 25 % de los casos. Esta frecuencia concuerda con lo comunicado en la literatura hasta el momento.
Acute lymphocytic leukemia (ALL) represents approximately 80% of the pediatric leukemias.The existance of a cryptic translocation, the t (12;21) (p12;q22) in the type B ALL, which is not detected by the conventional cytogenetic techniques and involve the TEL and AML1 oncogenes, has been recently shown by molecular biology. This alteration is at present the most common in this leukemia and it is observed approximately in 25% of the cases. Some authors have stated that such translocation identifies a group of patients with a very favorable evolution and that's why it is considered as an indicator of good prognosis. The determination of the t (12;21) in the study of ALL has a prognostic importance and it also serves as a marker for the detection of the minimal residual disease. In our paper, we standardized the RT-PCR technique for the detection of the t (12;21) and we also analized samples from 20 pediatric patients with type B ALL, which at the time of the study was in the phase of initial diagnosis or on relapse. In the study, 5 of the 20 patients showed rearranged TEL/AML l genes, which accounted for 25% of the cases. This frequency agrees with what is reported in literature up to now.