RESUMEN

Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML subtypes. This classification highlights crucial genetic markers such as FLT3, NPM1 mutations, and MLL-AF9 fusion, which are essential for prognosis and directing targeted therapies. The MLL-AF9 fusion protein is often linked with therapy-resistant AML, highlighting the risk of relapse due to standard chemotherapeutic regimes. In this sense, factors like the ZEB, SNAI, and TWIST gene families, known for their roles in epithelial-mesenchymal transition (EMT) and cancer metastasis, also regulate hematopoiesis and may serve as effective therapeutic targets in AML. These genes contribute to cell proliferation, differentiation, and extramedullary hematopoiesis, suggesting new possibilities for treatment. Advancing our understanding of the molecular mechanisms that promote AML, especially how the bone marrow microenvironment affects invasion and drug resistance, is crucial. This comprehensive insight into the molecular and environmental interactions in AML emphasizes the need for ongoing research and more effective treatments.

RESUMEN

BACKGROUND: The involvement of the KMT2 methyltransferase family in the pathogenesis of head and neck squamous cell carcinoma (HNSCC) remains elusive. METHOD: This study adhered to the PRISMA guidelines, employing a search strategy in the LIVIVO, PubMed, Scopus, Embase, Web of Science, and Google Scholar databases. The methodological quality of the studies was assessed by the Joanna Briggs Institute. RESULTS: A total of 33 studies involving 4294 individuals with HNSCC were included in this review. The most important alteration was the high mutational frequency in the KMT2C and KMT2D genes, with reported co-occurrence. The expression of the KMT2D gene exhibited considerable heterogeneity across the studies, while limited data was available for the remaining genes. CONCLUSIONS: KMT2C and KMT2D genes seem to have tumor suppressor activities, with involvement of cell cycle inhibitors, regulating different pathways that can lead to tumor progression, disease aggressiveness, and DNA damage accumulation.

Asunto(s)

Neoplasias de Cabeza y Cuello , Metiltransferasas , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/genética , Genes Supresores de Tumor

RESUMEN

The KMT2A (MLL) gene rearrangements (KMT2A-r) are associated with a diverse spectrum of acute leukemias. Although most KMT2A-r are restricted to nine partner genes, we have recently revealed that KMT2A-USP2 fusions are often missed during FISH screening of these genetic alterations. Therefore, complementary methods are important for appropriate detection of any KMT2A-r. Here we use a machine learning model to unravel the most appropriate markers for prediction of KMT2A-r in various types of acute leukemia. A Random Forest and LightGBM classifier was trained to predict KMT2A-r in patients with acute leukemia. Our results revealed a set of 20 genes capable of accurately estimating KMT2A-r. The SKIDA1 (AUC: 0.839; CI: 0.799-0.879) and LAMP5 (AUC: 0.746; CI: 0.685-0.806) overexpression were the better markers associated with KMT2A-r compared to CSPG4 (also named NG2; AUC: 0.722; CI: 0.659-0.784), regardless of the type of acute leukemia. Of importance, high expression levels of LAMP5 estimated the occurrence of all KMT2A-USP2 fusions. Also, we performed drug sensitivity analysis using IC50 data from 345 drugs available in the GDSC database to identify which ones could be used to treat KMT2A-r leukemia. We observed that KMT2A-r cell lines were more sensitive to 5-Fluorouracil (5FU), Gemcitabine (both antimetabolite chemotherapy drugs), WHI-P97 (JAK-3 inhibitor), Foretinib (MET/VEGFR inhibitor), SNX-2112 (Hsp90 inhibitor), AZD6482 (PI3Kß inhibitor), KU-60019 (ATM kinase inhibitor), and Pevonedistat (NEDD8-activating enzyme (NAE) inhibitor). Moreover, IC50 data from analyses of ex-vivo drug sensitivity to small-molecule inhibitors reveals that Foretinib is a promising drug option for AML patients carrying FLT3 activating mutations. Thus, we provide novel and accurate options for the diagnostic screening and therapy of KMT2A-r leukemia, regardless of leukemia subtype.

RESUMEN

Therapy-related acute myeloid leukemia (t-AML) following treatment with topoisomerase-II inhibitors has been increasingly reported. These compounds (e.g. etoposide) promote DNA damage and are associated with KMT2A rearrangements. They are widely used as first-line treatment in hemophagocytic lymphohistiocytosis (HLH). Here we describe a newborn who developed t-AML after HLH treatment. We provide detailed clinical, cytogenetic, and molecular characteristics of this patient, including the identification of a novel gene fusion - KMT2A-SNX9 - in t-AML. Considering the dismal outcome of this case, we discuss the side-effects of etoposide administration during HLH treatment in infants.

Asunto(s)

Diploidia , Cariotipo , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mieloide Aguda/genética , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Secuencia de Bases , Niño , Resultado Fatal , Humanos , Lactante , Recién Nacido , Masculino

RESUMEN

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.

RESUMEN

Pesticides are commonly used worldwide and almost every human is potentially exposed to these chemicals. Exposure to pesticides such as permethrin and malathion has been associated with hematological malignancies in epidemiological studies. However, biological evidence showing if these chemicals induce genetic aberrations involved in the etiology of leukemia and lymphoma is missing. In our previous work, we have shown that a single high exposure (200 µm, 24 hours) of permethrin and malathion induce damage in genes associated with hematological malignancies in peripheral blood mononuclear cells analyzed by interphase fluorescence in situ hybridization (FISH). In the present study, we assessed by FISH whether exposure to low concentrations (0.1 µm, 72 hours) of permethrin and malathion induce aberrations in KMT2A and IGH genes, which are involved in the etiology of leukemia and lymphoma. Peripheral blood mononuclear cells were exposed to the chemicals, and damage in these genes was assessed on interphases and metaphases. We observed that both chemicals at low concentration induced structural aberrations in KMT2A and IGH genes. A higher level of damage was observed in KMT2A gene with malathion treatment and in IGH gene with permethrin exposure. We also observed numerical aberrations induced by these chemicals. The most frequent aberrations detected on interphase FISH were also observed on metaphases. Our results show that permethrin and malathion induce genetic damage in genes associated with hematological cancer, at concentrations biologically relevant. In addition, damage was observed on dividing cells, which suggests that these cells maintain their proliferation capacity in spite of the genetic damage they possess.

Asunto(s)

Daño del ADN , Genes de las Cadenas Pesadas de las Inmunoglobulinas , N-Metiltransferasa de Histona-Lisina/genética , Insecticidas/toxicidad , Leucemia/inducido químicamente , Leucocitos Mononucleares/efectos de los fármacos , Linfoma/inducido químicamente , Malatión/toxicidad , Proteína de la Leucemia Mieloide-Linfoide/genética , Permetrina/toxicidad , Proliferación Celular , Supervivencia Celular , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Hibridación Fluorescente in Situ , Interfase , Leucemia/enzimología , Leucemia/genética , Leucemia/patología , Leucocitos Mononucleares/enzimología , Leucocitos Mononucleares/patología , Linfoma/enzimología , Linfoma/genética , Linfoma/patología , Masculino , Metafase , Índice Mitótico , Medición de Riesgo

RESUMEN

Experimental and epidemiological data have shown that acute myeloid leukemia in early-age (i-AML) originates prenatally. The risk association between transplacental exposure to benzene metabolites and i-AML might be influenced by genetic susceptibility. In this study, we investigated the relationship between genetic polymorphisms in CYP2E1, EPHX1, MPO, NQO1, GSTM1 and GSTT1 genes, and i-AML risk. The study included 101 i-AMLs and 416 healthy controls. Genomic DNA from study subjects was purified from bone marrow or peripheral blood aspirates and genotyped for genetic polymorphisms by real-time PCR allelic discrimination, Sanger sequencing and multiplex PCR. Crude and adjusted odds ratios (OR, adjOR, respectively) with 95% confidence intervals (95% CI) were assessed using unconditional logistic regression to estimate the magnitude of risk associations. EPHX1 rs1051740 T>C was associated with i-AML risk under the co-dominant (adjOR 3.04, P = 0.003) and recessive (adjOR 2.99, P = 0.002) models. In stratified analysis, EPHX1 rs1051740 was associated with increased risk for i-AML with KMT2A rearrangement (adjOR 3.06, P = 0.045), i-AML with megakaryocytic differentiation (adjOR 5.10, P = 0.008), and i-AML with type I mutation (adjOR 2.02, P = 0.037). EPHX1 rs1051740-rs2234922 C-G haplotype was also associated with increased risk for i-AML (adjOR 2.55, P = 0.043), and for i-AML with KMT2A rearrangement (adjOR 3.23, P = 0.034). Since EPHX1 enzyme is essential in cellular defense against epoxides, the diminished enzymatic activity conferred by the variant allele C could explain the risk associations found for i-AML. In conclusion, EPHX1 rs1051740 plays an important role in i-AML's genetic susceptibility by modulating the carcinogenic effects of epoxide exposures in the bone marrow.

Asunto(s)

Epóxido Hidrolasas/genética , Reordenamiento Génico , Predisposición Genética a la Enfermedad , N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Lactante , Masculino

RESUMEN

Childhood acute lymphoblastic leukaemia (ALL) with MLL rearrangement (MLL-r) is an aggressive disease still associated with a high mortality rate. Recent investigations have identified co-operating mutations in the RAS pathway and although the functional consequences of these mutations are not yet fully understood, aberrant regulation of RAS pathway signalling at both transcriptional and protein levels is observed. Studies investigating the efficacy of specific inhibitors of this pathway, e.g. MEK-inhibitors, have also achieved encouraging results. In this context, this mini-review summarizes the available data surrounding MLL-r infant ALL with RAS mutation in relation to other well-known features of this intriguing disease.

Asunto(s)

Reordenamiento Génico , Genes ras , N-Metiltransferasa de Histona-Lisina/genética , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores

RESUMEN

Chronic myeloid leukemia (CML) is characterized by the translocation t(9;22)(q34;q11) [Philadelphia (Ph) chromosome). Although not frequently occurring, additional chromosome abnormalities (ACAs) can be detected at diagnosis and a number have been associated with an adverse cytogenetic and molecular outcome. The present study reports a case of CML presenting with the translocation t(1;11)(q21;q23) and a cryptic Ph chromosome. The presence of ACAs could generate greater genetic instability, promoting the emergence of further alterations. The present findings suggest that t(1;11)(q21;q23) can prevent a good response to tyrosine kinase inhibitor (TKI) therapy developing a primary resistance. In the present patient, at a recent follow-up, the T315I mutation was detected. This mutation confers full resistance to all available TKI, except ponatinib, which was not a therapeutic option due to comorbidities.

RESUMEN

In pediatric acute leukemias, reciprocal chromosomal translocations frequently cause gene fusions involving the lysine (K)-specific methyltransferase 2A gene (KMT2A, also known as MLL). Specific KMT2A fusion partners are associated with the disease phenotype (lymphoblastic vs. myeloid), and the type of KMT2A rearrangement also has prognostic implications. However, the KMT2A partner gene cannot always be identified by banding karyotyping. We sought to identify such partner genes in 13 cases of childhood leukemia with uninformative karyotypes by combining molecular techniques, including multicolor banding FISH, reverse-transcriptase PCR, and long-distance inverse PCR. Of the KMT2A fusion partner genes, MLLT3 was present in five patients, all with acute lymphoblastic leukemia, MLLT1 in two patients, and MLLT10, MLLT4, MLLT11, and AFF1 in one patient each. Reciprocal reading by long-distance inverse PCR also disclosed KMT2A fusions with PITPNA in one patient, with LOC100132273 in another patient, and with DNA sequences not compatible with any gene in three patients. The most common KMT2A breakpoint region was intron/exon 9 (3/8 patients), followed by intron/exon 11 and 10. Finally, multicolor banding revealed breakpoints in other chromosomes whose biological and prognostic implications remain to be determined. We conclude that the combination of molecular techniques used in this study can efficiently identify KMT2A fusion partners in complex pediatric acute leukemia karyotypes. Copyright © 2016 John Wiley & Sons, Ltd.

Asunto(s)

N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Niño , Preescolar , Citogenética , Humanos , Lactante , Cariotipo , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/patología , Masculino

RESUMEN

Resumen El síndrome de Kabuki (SK) es una patología muy rara, descrita por primera vez en 1981 por Niikawa y Kuroki en Japón. Se han publicado cerca de 400 casos a nivel mundial. En Colombia se conocen cinco casos diagnosticados y publicados; el caso objeto de este estudio sería el sexto en nuestro país. Presentamos la descripción del caso de una paciente de 2 años y 6 meses con rasgos dismórficos compatibles con síndrome de Kabuki. Examen físico: fisuras palpebrales elongadas, eversión del tercio lateral párpado inferior, cejas arqueadas con tercio lateral más despoblado, puente nasal deprimido, boca en carpa, paladar hendido, pabellones auriculares de baja implantación con rotación posterior. El síndrome de Kabuki se caracteriza por sus anomalías faciales peculiares que se consideran son la única manifestación que puede orientar al diagnóstico del mismo sin excepciones. Recientemente se han identificado mutaciones sin sentido y de corrimiento del marco de lectura, entre otras en el gen MLL2 en aproximadamente el 75 % de los casos y en una menor proporción deleciones y mutaciones sin sentido en el gen KDM6A.

---

Abstract Kabuki syndrome is a rare disease described by Kuroki and Niikawa in Japanese population in 1981. There are over 400 cases over the world and 5 cases described in Colombian population. Therefore this is the 6th Kabuki syndrome found in Colombia. We report a 2 years old female with Kabuki syndrome phenotype. Clinical examination showed: long palpebral fissures with eversion of the lateral third of the lower eyelids, a broad and depressed nasal tip, left palate and low setup ears. Kabuki syndrome includes facial features whit specific characteristics enough to classify the patients. However, there are some mutations in MLL2 gene present in almost 75 % of Kabuki syndrome. In addition there are some deletion and duplications abnormalities in KMD6A gene described in Kabuki syndrome patients.

RESUMEN

Rearrangement of the mixed lineage-leukemia gene (MLL-r) is common in hematological diseases and is generally associated with poor prognosis. The mixed-lineage leukemia gene translocated to, 3 (MLLT3) gene (9p22) is a frequent MLL-r partner (∼18% of leukemias with MLL rearrangement) and is characterized by the translocation t(9;11) (p22;q23), forming an MLL-MLLT3 gene fusion. MLL-r are usually simple reciprocal translocations between two different chromosomes, although karyotypes with complex MLL-r have been observed. We present a rare case of a child with acute lymphoblastic leukemia with a complex karyotype in which the classical t(9;11) (p22;q23) was cryptically relocated into a third chromosome in a balanced three-way translocation. At the genome level, however, the MLL-MLLT3 three-way translocation still displayed both reciprocal fusion transcripts. This argues in favor for a model where a simple two-way t(9;11) (p22;q23) was likely the first step that then evolved in to a more complex karyotype. Multicolor banding techniques can be used to greatly refine complex karyotypes and its chromosomal breakpoints. Also in the presence of putative new rearrangements, Long distance inverse-PCR is an important tool to identify which gene fusion is involved.

Asunto(s)

Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Preescolar , Femenino , Humanos , Cariotipo , Translocación Genética

Asunto(s)

Genes ras , N-Metiltransferasa de Histona-Lisina/genética , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética , Humanos , Lactante

RESUMEN

The clinical and molecular findings of 77 cases of neonatal leukemia (NL) and 380 of infant leukemia (IL) were selected to distinguish features between NL and IL. Somatic gene mutations associated with acute leukemia including FLT3, RAS and PTPN11 were revisited. There were 42 cases of congenital leukemia associated with Down syndrome (DS) and 39 of these cases presented features of acute myeloid leukemia (AML)-M7. Twenty-seven of the DS cases underwent spontaneous remission and were reclassified as a transient myeloproliferative disorder. GATA1 mutations were found in 70% of these cases. In non-DS, frequent abnormalities were MLL rearrangements, mainly MLL-AFF1 in acute lymphoblastic leukemia and MLL-MLLT3 in AML. The FLT3 mutation was not found, while RAS (n = 4) and PTPN11 (n = 2) mutations were identified and reported for the first time in NL. There was substantial evidence to support that somatic abnormalities occur in utero. Thus, congenital leukemia is a good model for understanding leukemogenesis.

Asunto(s)

Leucemia/epidemiología , Leucemia/genética , Mutación , Brasil/epidemiología , Análisis Citogenético/métodos , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Factor de Transcripción GATA1/genética , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Leucemia/tratamiento farmacológico , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Leucemia Megacarioblástica Aguda/epidemiología , Leucemia Megacarioblástica Aguda/genética , Masculino , Epidemiología Molecular , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Tirosina Quinasa 3 Similar a fms/genética , Proteínas ras/genética

RESUMEN

The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid-induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline-based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2-year overall survival (OS) (P = 0·005) and 2-year disease-free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2-year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71-30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08-0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49-43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05-0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99-1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Unión al ADN/metabolismo , Leucemia Promielocítica Aguda/tratamiento farmacológico , Adolescente , Adulto , Antraciclinas/administración & dosificación , Estudios de Casos y Controles , Femenino , Humanos , Leucemia Promielocítica Aguda/metabolismo , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Tretinoina/administración & dosificación , Adulto Joven

Asunto(s)

Cromosomas Humanos Par 11/genética , Amplificación de Genes , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Trisomía , Adolescente , Bandeo Cromosómico , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación Fluorescente in Situ , Cariotipo

RESUMEN

Catalogar a variabilidade fenotípica dos pacientes com síndrome de Kabuki atendidos no Núcleo de Genética da Secretaria de Estado de Saúde do Distrito Federal, e comparar os resultados com os dados disponíveis na literatura.

---

To catalog the phenotypic variability of patients with Kabuki syndrome seen at the Clinical Genetics Service of Secretaria de Estado de Saúde do Distrito Federal, and to compare the results with data available in the literature.

RESUMEN

Learning and memory are basic functions of the brain that allowed human evolution. It is well accepted that during learning and memory formation the dynamic establishment of new active synaptic connections is crucial. Persistent synaptic activation leads to molecular events that include increased release of neurotransmitters, increased expression of receptors on the postsynaptic neuron, thus creating a positive feedback that results in the activation of distinct signaling pathways that temporally and permanently alter specific patterns of gene expression. However, the epigenetic changes that allow the establishment of long term genetic programs that control learning and memory are not completely understood. Even less is known regarding the signaling events triggered by synaptic activity that regulate these epigenetic marks. Here we review the current understanding of the molecular mechanisms controlling activity-dependent gene transcription leading synaptic plasticity and memory formation. We describe how Ca(2+) entry through N-methyl-d-aspartate-type glutamate neurotransmitter receptors result in the activation of specific signaling pathways leading to changes in gene expression, giving special emphasis to the recent data pointing out different epigenetic mechanisms (histone acetylation, methylation and phosphorylation as well as DNA methylation and hydroxymethylation) underlying learning and memory.

Asunto(s)

Epigénesis Genética/fisiología , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Transcripción Genética , Animales , Humanos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/fisiología , Transducción de Señal/fisiología

RESUMEN

Translocations involving MLL gene are common among children with acute leukemias. Most importantly, the presence of a given MLL fusion partner dictates the outcome of patients. Patients with complex MLL rearrangements, e.g. three-way translocations could be related to a poor clinical outcome. For this purpose, we characterize 5 childhood patients with three-way translocations involving MLL gene. By LDI-PCR we identified 15 out of 17 fusion alleles and determined the localization of these breakpoints. In all cases at least one functional MLL fusion allele was present. In addition, patients displayed a remaining 3'-MLL allele that allow in principle the expression of the MLL* protein variant.

Asunto(s)

Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética , Secuencia de Bases , Preescolar , Femenino , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Proteínas de Fusión Oncogénica/genética , Reacción en Cadena de la Polimerasa/métodos

RESUMEN

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.