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Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulated NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, and the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and we evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced the activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased the secretion of seven cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy.
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Imiquimode , Células Matadoras Naturais , Ativação Linfocitária , Poli I-C , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Toll-Like , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Poli I-C/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Imiquimode/farmacologia , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Criança , Oligodesoxirribonucleotídeos/farmacologia , Citocinas/metabolismo , Feminino , Interferon gama/metabolismo , Masculino , Imidazóis/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Pré-Escolar , Agonistas do Receptor Semelhante a TollRESUMO
It is important to study the relationship between extremely low-frequency magnetic fields (ELF-MFs) and childhood leukemia, particularly in locations with a high incidence of this neoplasm in children and an elevated exposure to ELF-MF, such as Mexico City. The aim was to investigate the association between ELF-MF exposure and the risk of B-lineage acute lymphoblastic leukemia (B-ALL). A case-control study was conducted in Mexico City during the period from 2010 to 2011. Residential 24-h ELF-MF measurements were obtained for 290 incident B-ALL patients and 407 controls, aged less than 16 years. Controls were frequency-matched by sex, age (±18 months), and health institution. The adjusted odds ratios (aOR) and 95% confidence intervals (CIs) were calculated. ELF-MF exposure at <0.2 µT was used to define the reference group. ELF-MF exposure at ≥0.3 µT was observed in 11.3% of the controls. Different ELF-MF intensity cutoff values were used to define the highest exposure category; the highest exposure category for each cutoff value was associated with an increased risk of B-ALL compared with the corresponding lower exposure categories. The aORs were as follows: ≥0.2 µT = 1.26 (95% CI: 0.84-1.89); ≥0.3 µT = 1.53 (95% CI: 0.95-2.48); ≥0.4 µT = 1.87 (95% CI: 1.04-3.35); ≥0.5 µT = 1.80 (95% CI 0.95-3.44); ≥0.6 µT = 2.32 (95% CI: 1.10-4.93). ELF-MF exposure as a continuous variable (per 0.2 µT intervals) was associated with B-ALL risk (aOR = 1.06; 95% CI: 1.01-1.12). In the present study, the proportion of children exposed to ≥0.3 µT is among the highest reported worldwide. Additionally, an ELF-MF exposure ≥0.4 µT may be associated with the risk of B-ALL. Bioelectromagnetics. © 2020 Bioelectromagnetics Society.
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Exposição Ambiental/efeitos adversos , Campos Magnéticos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Cidades/epidemiologia , Feminino , Humanos , Incidência , MasculinoRESUMO
BACKGROUND: Mexico City has one of the highest incidences and mortality rates of acute lymphoblastic leukemia (ALL) in the world and a high frequency of early relapses (17%) and early mortality (15%). Otherwise, childhood overweight and obesity are reaching epidemic proportions. They have been associated with poor outcomes in children with ALL. The aim of present study was to identify if overweight and obesity are predictors of early mortality and relapse in Mexican children with ALL. METHODS: A multicenter cohort study was conducted. ALL children younger than 15 years old were included and followed-up during the first 24 months after diagnosis. Overweight and obesity were classified according World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) criteria. Early mortality and early relapses were the main outcomes. RESULTS: A total of 1070 children were analyzed. Overweight/obesity at diagnosis were predictors of early mortality (WHO: HR = 1.4, 95%CI:1.0-2.0; CDC: HR = 1.6, 95%CI:1.1-2.3). However, no associations between overweight (WHO: HR = 1.5, 95%CI:0.9-2.5; CDC: HR = 1.0; 95% CI:0.6-1.6) and obesity (WHO: HR = 1.5, 95%CI:0.7-3.2; CDC: HR = 1.4; 95%CI:0.9-2.3) with early relapse were observed. CONCLUSIONS: Overweight and obese patients embody a subgroup with high risk of dying during leukemia treatment.
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Obesidade Infantil/epidemiologia , Obesidade Infantil/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Incidência , Lactente , Masculino , México/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , RecidivaRESUMO
Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized that chromosomal translocations are important in cancer etiology. Specific fusion genes have been considered as important treatment targets in childhood acute lymphoblastic leukemia (ALL). The present research aimed at the identification and characterization of novel fusion genes with potential clinical implications in Mexican children with acute lymphoblastic leukemia. The RNA-sequencing approach was used. Four fusion genes not previously reported were identified: CREBBP-SRGAP2B, DNAH14-IKZF1, ETV6-SNUPN, ETV6-NUFIP1. Although a fusion gene is not sufficient to cause leukemia, it could be involved in the pathogenesis of the disease. Notably, these new translocations were found in genes encoding for hematopoietic transcription factors which are known to play an important role in leukemogenesis and disease prognosis such as IKZF1, CREBBP, and ETV6. In addition, they may have an impact on the prognosis of Mexican pediatric patients with ALL, with the potential to be included in the current risk stratification schemes or used as therapeutic targets.
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Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Adolescente , Adulto , Proteína de Ligação a CREB/genética , Criança , Pré-Escolar , Dineínas/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Humanos , Fator de Transcrição Ikaros/genética , Lactente , Masculino , México , Proteínas Nucleares/genética , Prognóstico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas de Ligação ao Cap de RNA/genética , Proteínas de Ligação a RNA/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Adulto Jovem , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
INTRODUCTION: Acute myeloid leukemias represent the second most common childhood leukemia subtype. In Mexico, there are few studies on descriptive epidemiology for this disease. AIMS: To report acute myeloid leukemia incidence for children less than 15 years of age in the Metropolitan Area of the Valley of Mexico for a period of five years (2010-2014) and to analyze whether there are differences in the incidence of acute myeloid leukemia by regions. MATERIAL AND METHODS: A descriptive study was conducted in nine public hospitals in Mexico City. The crude annual average incidence rate and adjusted average annual incidence rate were calculated. RESULTS: A total of 190 patients with diagnosis of de novo acute myeloid leukemia were analyzed. Male sex (57.2%) and acute myeloid leukemia-M3 subtype (25.3%) were more frequent. The adjusted average annual incidence rates for Mexico City and for the Metropolitan Area of the Valley of Mexico were 8.18 and 7.74 per million children under 15 years old, respectively. CONCLUSIONS: It seems that childhood acute myeloid leukemia incidence is increasing in Mexico City, which makes the identification of associated risk factors imperative.
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Leucemia Mieloide Aguda/epidemiologia , Adolescente , Criança , Cidades/epidemiologia , Humanos , Incidência , Lactente , Leucemia Mieloide Aguda/etiologia , Masculino , México/epidemiologia , Fatores de Risco , Distribuição por SexoRESUMO
Introduction: Acute leukemias (AL) are the main types of cancer in children worldwide. In Mexico, they represent one of the main causes of death in children under 20 years of age. Most of the studies on the incidence of AL in Mexico have been developed in the urban context of Greater Mexico City and no previous studies have been conducted in the central-south of the country through a population-based study. The aim of the present work was to identify the general and specific incidence rates of pediatric AL in three states of the south-central region of Mexico considered as some of the marginalized populations of Mexico (Puebla, Tlaxcala, and Oaxaca). Methods: A population-based study was conducted. Children aged less than 20 years, resident in these states, and newly diagnosed with AL in public/private hospitals during the period 2021-2022 were identified. Crude incidence rates (cIR), standardized incidence rates (ASIRw), and incidence rates by state subregions (ASIRsr) were calculated. Rates were calculated using the direct and indirect method and reported per million children under 20 years of age. In addition, specific rates were calculated by age group, sex, leukemia subtype, and immunophenotype. Results: A total of 388 cases with AL were registered. In the three states, the ASIRw for AL was 51.5 cases per million (0-14 years); in Puebla, it was 53.2, Tlaxcala 54.7, and Oaxaca de 47.7. In the age group between 0-19 years, the ASIRw were 44.3, 46.4, 48.2, and 49.6, in Puebla, Tlaxcala, and Oaxaca, respectively. B-cell acute lymphoblastic leukemia was the most common subtype across the three states. Conclusion: The incidence of childhood AL in the central-south region of Mexico is within the range of rates reported in other populations of Latin American origin. Two incidence peaks were identified for lymphoblastic and myeloid leukemias. In addition, differences in the incidence of the disease were observed among state subregions which could be attributed to social factors linked to the ethnic origin of the inhabitants. Nonetheless, this hypothesis requires further investigation.
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Background: A heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC). Methods: A population-based case-control study was conducted. Children <18 years old, newly diagnosed with ALL and residents of GMC were included. Controls were patients without leukemia recruited from second-level public hospitals, frequency-matched by sex, age, and health institution with the cases. The residence address where the patients lived during the last year before diagnosis (cases) or the interview (controls) was used for geolocation. Kulldorff's spatial scan statistic was used to detect spatial clusters (SCs). Relative risks (RR), associated p-value and number of cases included for each cluster were obtained. Results: A total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (p<0.0001) was observed for the main cluster. Similar results were noted for the remaining seven ones. Additionally, a proximity between SCs, electrical installations and petrochemical facilities was observed. Conclusions: The identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL.
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Chromosomal translocation-generated fusion genes in childhood acute lymphoblastic leukemia (ALL) are well-known indicators of prognostic outcome. This study was conducted to establish the clinical relevance of the fusion genes distribution pattern in Mexican children with newly diagnosed ALL. Multiplex RT-PCR assays were used to detect 4 commonest fusion transcripts in 261 Mexican children with B-cell precursor ALL aged 1 to 14 years old, comparing differences in the distribution of the patients between molecular subgroups to a common collection of clinical parameters. We documented a 13% significant proportion of all patients who are more than 10 years of age, harboring fusion transcripts associated with leukocytosis and poor response to remission-induction chemotherapy, than those negative children for chimeric transcripts (P<0.001). Most notable observation was identified a significant number of e2a-pbx1-positive patients who showed a more aggressive disease at diagnosis. As presented here, this report gives an overview of the clinical implications of the fusion gene positivity in Mexican children with ALL in the context of traditional risk stratification variables. Our data support the existence of important ethnic and geographic differences in Mexican population.
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Cromossomos Humanos/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Criança , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Proteínas de Homeodomínio/genética , Humanos , Imunofenotipagem , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
INTRODUCTION: Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia (AML) characterized by chromosomal translocations involving the retinoid acid receptor α (RARA) gene on chromosome 17. APL is a relatively rare blood disease that is highly curable with current treatment strategies; however, patient outcomes are heterogeneous in countries with limited resources. Promyelocytic leukemia accounts for 20-25% of all AML cases in Latin American countries. MATERIAL AND METHODS: We conducted a study from July 2007 to July 2012 and applied the IC-APL2006 protocol. This case study reports the results from eleven patients with AML M3 (five males and six females). In all cases, the diagnoses were made by aspirating bone marrow and evaluating the t(15:17) or t(11:17) transcript. In eight cases, the molecular biology-based diagnostics for the PLM-RARa transcript were positive, and they were negative in two cases. One patient was positive for the PLZF-RARa transcript. RESULTS: The mean WBC at the time of diagnosis was 10.1 x 10(9)/L, and the mean platelet count was 17.1 x 10(9)/L. The mean percentage of abnormal promyelocytes in the bone marrow aspirates was 68%. Of the eleven patients, four presented with disseminated intravascular coagulation. All of the patients began treatment with transretinoic acid (ATRA) (45 mg/m(2)/day), which led to 4 cases of ATRA syndrome. There were 2 relapses, and the patient died in one case. The remaining ten patients were alive after the median follow-up period of 33.6 months (range from 11 to 60 months). CONCLUSION: The authors report on a series of cases involving pediatric patients with AML M3 seen at a single institution; the patients were stratified and treated with a standard protocol to obtain satisfactory results. Although the number of patients is limited, the health outcomes are relevant. To our knowledge, this is the first series of pediatric APL patients in Mexico who were treated with the IC-APL2006 protocol.
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Leucemia Promielocítica Aguda/epidemiologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Coagulação Intravascular Disseminada/etiologia , Feminino , Seguimentos , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , México/epidemiologia , Mitoxantrona/administração & dosagem , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genética , Recidiva , Indução de Remissão , Resultado do Tratamento , Tretinoína/efeitos adversos , Tretinoína/uso terapêuticoRESUMO
BACKGROUND: Thiopurine S-Methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs, such as 6-mercaptopurine, 6-thioguanine and azathioprine, leading to their inactivation. Individuals who carry TPMT allele variants are more likely to experience life-threatening toxicity when these drugs are given at a standard dose. Wildtype phenotype TPMT*1 exhibits high level of catalytic activity, while all variants manifest with a decreased enzymatic activity. Ethnic-related differences in the distribution of TPMT variant alleles have been found. In Mexico, limited information is available; so far only two studies have been published and clear differences exist between them. MATERIAL AND METHODS: Allelic variants and genotypes of the TPMT gene were determined in 240 Mexican children with leukemia and solid tumors using DNA extracted from peripheral blood. Polymorphisms G460A and A719G were identified by PCR-RFLP and G238C by the specific-allele PCR assay. The enzyme variants were detected by allelic discrimination. RESULTS: Homozygous wild-type genotype TPMT*1/TPMT*1 was found in 173 patients (72.1%); 67 cases (27.9%) were heterozygous: 18 with genotype TPMT*1/TPMT*3B (7.5%), 17 TPMT*1/TPMT*3C (7.1%), 16 TPMT*1/TMPT*2 (6.7%), 14 TPMT*1/TPMT*3A (5.8%), and 2 (0.8%) were homozygous for two variants: TPMT*2/ TPMT*3B in both. The allele frequencies were TPMT*1 in 411 (85.62%), TPMT*3B in 20 (4.1%), TPMT*2 in 18 (3.75%), TPMT*3C in 17 (3.55%) and TPMT*3A in 14 (2.9%). CONCLUSIONS: A high frequency and diversity of variant TPMT genotypes was found in this series with predominance of the TPMT*3B allele.
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Metiltransferases/genética , Neoplasias/genética , Polimorfismo Genético , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , MéxicoRESUMO
Introduction: Epidemiological studies around the world on acute leukemia (AL) and risk factors in infants are scarce. Infant AL has been proposed to originate in utero, which facilitates its study by establishing a short exposure time in pregnant women to environmental and dietary factors that could contribute to the risk of or protection against leukemia. We hypothesized that maternal diet during pregnancy may be an important factor involved in AL in offspring. Methods: We conducted a hospital-based case-control study from 2010 to 2019 on maternal diet during pregnancy in nine high-specialty public hospitals of different health institutions that diagnose and offer treatment to children with AL in Mexico City. Cases (n=109) were children ≤24 months of age with de novo diagnosis of AL, and controls (n=252) were children obtained in hospitals from second-level medical care matched for age, sex, and health institution. Maternal diet during pregnancy was obtained by a semiquantitative food frequency questionnaire. Unconditional logistic regression models were used to assess the association between food groups and infant AL. Potential confounders were assessed by constructing directed acyclic graphs (DAGs) with Dagitty software in which adjusted options were identified for the construction of unconditional logistic regression models. Results: Cases were slightly predominantly female (52.3%). The years of education of the mother in cases and controls was 0-9 on average, and those who reported smoking cigarettes and consuming alcohol during pregnancy did so at a low frequency. Regarding the mother's diet, the main findings were that the consumption of allium vegetables during pregnancy was inversely associated with AL for medium and high consumption (OR=0.26, 95% CI 0.14-0.46; P-trend< 0.001). In contrast, the high consumption of high-fat dairy products had a positive association with AL (OR=2.37, 95% CI 1.30-4.34; P-trend<0.001). No association was found between consumption of topoisomerase II inhibitor foods during pregnancy and AL. Conclusion: The results suggest that maternal intake during pregnancy of allium vegetables, specifically garlic, is inversely associated with the development of AL in children ≤24 months old. On the other hand, consumption of high-fat dairy products is positively associated with AL in children ≤24 months old.
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BACKGROUND: The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring. METHODS: The authors used a case-control study design to examine the association between retinoblastoma risk and maternal variations in the folate-metabolizing genes methylenetetrahydrofolate reductase (MTHFR) (a cytosine-to-thymine substitution at nucleotide 677 [MTHFR677CâT]; reference single nucleotide polymorphism rs1801133) and dihydrofolate reductase (DHFR) (a 19-base-pair deletion of intron 1a [DHFR19bpdel]; rs70991108). In central Mexico, 103 mothers of children with newly diagnosed unilateral retinoblastoma were enrolled in an institutional review board-approved study along with a control group of 97 mothers who had healthy children. Mothers were interviewed regarding perinatal characteristics, including use of prenatal vitamin supplements, and gave peripheral blood samples, which were used for polymerase chain reaction-based genotyping of rs1801133 and rs70991108. RESULTS: The risk of having a child with unilateral retinoblastoma was associated with maternal homozygosity for DHFR19bpdel (odds ratio, 3.78; 95% confidence interval, 1.89-7.55; P = .0002), even after controlling for the child's DHFR19bpdel genotype (odds ratio, 2.81; 95% confidence interval, 1.32-5.99; P = .0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel-associated risk was elevated significantly only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to the risk of having a child with retinoblastoma. CONCLUSIONS: Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biologic folate was associated with an increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population.
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Ácido Fólico/administração & dosagem , Polimorfismo de Nucleotídeo Único , Neoplasias da Retina/genética , Retinoblastoma/genética , Tetra-Hidrofolato Desidrogenase/genética , Estudos de Casos e Controles , Suplementos Nutricionais , Feminino , Ácido Fólico/metabolismo , Deleção de Genes , Genótipo , Humanos , Gravidez , Neoplasias da Retina/etiologia , Retinoblastoma/etiologia , RiscoRESUMO
Introduction: Over the years, the Hispanic population living in the United States has consistently shown high incidence rates of childhood acute leukemias (AL). Similarly, high AL incidence was previously observed in Mexico City (MC). Here, we estimated the AL incidence rates among children under 15 years of age in MC during the period 2010-2017. Methods: The Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia conducted a study gathering clinical and epidemiological information regarding children newly diagnosed with AL at public health institutions of MC. Crude age incidence rates (cAIR) were obtained. Age-standardized incidence rates worldwide (ASIRw) and by municipalities (ASIRm) were calculated by the direct and indirect methods, respectively. These were reported per million population <15 years of age; stratified by age group, sex, AL subtypes, immunophenotype and gene rearrangements. Results: A total of 903 AL cases were registered. The ASIRw was 63.3 (cases per million) for AL, 53.1 for acute lymphoblastic leukemia (ALL), and 9.4 for acute myeloblastic leukemia. The highest cAIR for AL was observed in the age group between 1 and 4 years (male: 102.34 and female: 82.73). By immunophenotype, the ASIRw was 47.3 for B-cell and 3.7 for T-cell. The incidence did not show any significant trends during the study period. The ASIRm for ALL were 68.6, 66.6 and 62.8 at Iztacalco, Venustiano Carranza and Benito Juárez, respectively, whereas, other municipalities exhibited null values mainly for AML. Conclusion: The ASIRw for childhood AL in MC is among the highest reported worldwide. We observed spatial heterogeneity of rates by municipalities. The elevated AL incidence observed in Mexican children may be explained by a combination of genetic background and exposure to environmental risk factors.
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Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Pré-Escolar , Cidades , Feminino , Humanos , Incidência , Lactente , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/etiologia , Masculino , México/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMO
Background: The distribution of RUNX1-RUNXT1, PML-RARA, CBFB-MYH11, BCR-ABL1p210 , and KMT2A-MLLT3 in the pediatric population with acute myeloid leukemia (AML) in many countries of Latin America is largely unknown. Therefore, we aimed to investigate the frequency of these fusion genes in children with de novo AML from Mexico City, which has one of the highest incidence rates of acute leukemia in the world. Additionally, we explored their impact in mortality during the first year of treatment. Methods: We retrospectively analyzed the presence of RUNX1-RUNXT1, PML-RARA, CBFB-MYH11, BCR-ABL1p210 , and KMT2A-MLLT3 by RT-PCR among 77 patients (<18 years) diagnosed with de novo AML between 2019 and 2021 in nine Mexico City hospitals. Results: The overall frequency of the fusion genes was 50.7%; RUNX1-RUNXT1 (22.1%) and PML-RARA (20.8%) were the most prevalent, followed by CBFB-MYH11 (5.2%) and BCR-ABL1p210 (2.4%). KMT2A-MLLT3 was not detected. Patients with PML-RARA showed the lowest survival with high early mortality events. However, more studies are required to evaluate the impact of analyzed fusion genes on the overall survival of the Mexican child population with AML. Conclusion: The pediatric population of Mexico City with AML had frequencies of AML1-ETO, PML-RARA, CBFB-MYH11, and BCR-ABL1p210 similar to those of other populations around the world. Patients with BCR-ABL1p210 and CBFB-MYH11 were few or did not die, while those with MLL-AF9 was not detected. Although patients with PML-RARA had a low survival and a high early mortality rate, further studies are needed to determine the long-term impacts of these fusion genes on this Latino population.
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ETV6::RUNX1 is a genetic rearrangement of good prognosis in children with acute lymphoblastic leukemia (ALL). In Mexico, its prevalence is low in comparison with Caucasian populations. We developed a novel TaqMan one-step RT-qPCR approach to assess the prevalence of four genetic rearrangements in a cohort of Hispanic children with ALL from Mexico City. The prevalence of common fusion gene transcripts was as follows: TCF3::PBX1 7.7%; BCR::ABL1p 190 3.3%; and KMT2A::AFF1 2.8%, and ETV6::RUNX1was observed with low prevalence (10.5%) in comparison to that reported for developed countries. This is consistent with previous findings on Mexican children with ALL and similar to those reported on children from Hispanic populations. The confirmation of a low prevalence of ETV6::RUNX1 in children of a Hispanic origin represents an advancement in the description of genetic factors of ALL in these populations.
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Background: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent pediatric cancer worldwide. Despite improvements in treatment regimens, approximately 20% of the cases cannot be cured, highlighting the necessity for identifying new biomarkers to improve the current clinical and molecular risk stratification schemes. We aimed to investigate whether LINC00173 is a biomarker in ALL and to explore its expression level in other human cancer types. Methods: A nested case-control study including Mexican children with BCP-ALL was conducted. LINC00173 expression was evaluated by qRT-PCR using hydrolysis probes. To validate our findings, RNA-seq expression data from BCP-ALL and normal tissues were retrieved from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Genotype-Tissue Expression (GTEx) repositories, respectively. LINC00173 expression was also evaluated in solid tumors by downloading available data from The Cancer Genome Atlas (TCGA). Results: A lower expression of LINC00173 in BCP-ALL cases compared to normal subjects was observed (p < 0.05). ALL patients who carry the TCF3/PBX1 fusion gene displayed lower expression of LINC00173 in contrast to other BCP-ALL molecular subtypes (p < 0.04). LINC00173 underexpression was associated with a high risk to relapse (HR = 1.946, 95% CI = 1.213-3.120) and die (HR = 2.073, 95% CI = 1.211-3.547). Patients with TCF3/PBX1 and underexpression of LINC00173 had the worst prognosis (DFS: HR = 12.24, 95% CI = 5.04-29.71; OS: HR = 11.19, 95% CI = 26-32). TCGA data analysis revealed that underexpression of LINC00173 is also associated with poor clinical outcomes in six new reported tumor types. Conclusion: Our findings suggest that LINC00173 is a biomarker of poor prognosis in BCP-ALL and other types of cancer. We observed an association between the expression of LINC00173 and TCF3/PBX1 and the risk to relapse and die in BCP-ALL, which is worse in TCF3/PBX1-positive cases displaying underexpression of LINC00173. Experimental studies are needed to provide insight into the LINC00173 and TCF3/PBX relationship.
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NK cells have unique attributes to react towards cells undergoing malignant transformation or viral infection. This reactivity is regulated by activating or inhibitory germline encoded receptors. An impaired NK cell function may result from an aberrant expression of such receptors, a condition often seen in patients with hematological cancers. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer worldwide and NK cells have emerged as crucial targets for developing immunotherapies. However, there are important gaps concerning the phenotype and behavior of NK cells during emergence of ALL. In this study we analyze the phenotype and function of NK cells from peripheral blood in pediatric patients with ALL at diagnosis. Our results showed that NK cells exhibited an altered phenotype highlighted by a significant reduction in the overall expression and percent representation of activating receptors compared to age-matched controls. No significant differences were found for the expression of inhibitory receptors. Moreover, NK cells with a concurrent reduced expression in various activating receptors, was the dominant phenotype among patients. An alteration in the relative frequencies of NK cells expressing NKG2A and CD57 within the mature NK cell pool was also observed. In addition, NK cells from patients displayed a significant reduction in the ability to sustain antibody-dependent cellular cytotoxicity (ADCC). Finally, an aberrant expression of activating receptors is associated with the phenomenon of leukemia during childhood.
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Background: In Mexico, the incidence of acute myeloid leukemia (AML) has increased in the last few years. Mortality is higher than in developed countries, even though the same chemotherapy protocols are used. CCAAT Enhancer Binding Protein Alpha (CEBPA) mutations are recurrent in AML, influence prognosis, and help to define treatment strategies. CEBPA mutational profiles and their clinical implications have not been evaluated in Mexican pediatric AML patients. Aim of the Study: To identify the mutational landscape of the CEBPA gene in pediatric patients with de novo AML and assess its influence on clinical features and overall survival (OS). Materials and Methods: DNA was extracted from bone marrow aspirates at diagnosis. Targeted massive parallel sequencing of CEBPA was performed in 80 patients. Results: CEBPA was mutated in 12.5% (10/80) of patients. Frameshifts at the N-terminal region were the most common mutations 57.14% (8/14). CEBPA biallelic (CEBPA BI) mutations were identified in five patients. M2 subtype was the most common in CEBPA positive patients (CEBPA POS) (p = 0.009); 50% of the CEBPA POS patients had a WBC count > 100,000 at diagnosis (p = 0.004). OS > 1 year was significantly better in CEBPA negative (CEBPA NEG) patients (p = 0.0001). CEBPA POS patients (either bi- or monoallelic) had a significantly lower OS (p = 0.002). Concurrent mutations in FLT3, CSF3R, and WT1 genes were found in CEBPA POS individuals. Their contribution to poor OS cannot be ruled out. Conclusion: CEBPA mutational profiles in Mexican pediatric AML patients and their clinical implications were evaluated for the first time. The frequency of CEBPA POS was in the range reported for pediatric AML (4.5-15%). CEBPA mutations showed a negative impact on OS as opposed to the results of other studies.
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BACKGROUND: Worldwide, acute leukemia is the most common type of childhood cancer. It is particularly common in the Hispanic populations residing in the United States, Costa Rica, and Mexico City. The objective of this study was to determine the incidence of acute leukemia in children who were diagnosed and treated in public hospitals in Mexico City. METHODS: Included in this study were those children, under 15 years of age and residents of Mexico City, who were diagnosed in 2006 and 2007 with leukemia, as determined by using the International Classification of Childhood Cancer. The average annual incidence rates (AAIR), and the standardized average annual incidence rates (SAAIR) per million children were calculated. We calculated crude, age- and sex-specific incidence rates and adjusted for age by the direct method with the world population as standard. We determined if there were a correlation between the incidence of acute leukemias in the various boroughs of Mexico City and either the number of agricultural hectares, the average number of persons per household, or the municipal human development index for Mexico (used as a reference of socio-economic level). RESULTS: Although a total of 610 new cases of leukemia were registered during 2006-2007, only 228 fit the criteria for inclusion in this study. The overall SAAIR was 57.6 per million children (95% CI, 46.9-68.3); acute lymphoblastic leukemia (ALL) was the most frequent type of leukemia, constituting 85.1% of the cases (SAAIR: 49.5 per million), followed by acute myeloblastic leukemia at 12.3% (SAAIR: 6.9 per million), and chronic myeloid leukemia at 1.7% (SAAIR: 0.9 per million). The 1-4 years age group had the highest SAAIR for ALL (77.7 per million). For cases of ALL, 73.2% had precursor B-cell immunophenotype (SAAIR: 35.8 per million) and 12.4% had T-cell immunophenotype (SAAIR 6.3 per million). The peak ages for ALL were 2-6 years and 8-10 years. More than half the children (58.8%) were classified as high risk. There was a positive correlation between the average number of persons per household and the incidence of the pre-B immunophenotype (Pearson's r, 0.789; P = 0.02). CONCLUSIONS: The frequency of ALL in Mexico City is among the highest in the world, similar to those found for Hispanics in the United States and in Costa Rica.
Assuntos
Leucemia Mieloide Aguda/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Imunofenotipagem , Incidência , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Masculino , México/epidemiologia , Fatores SocioeconômicosRESUMO
NK cells represent a heterogeneous subpopulation of lymphocytes of the innate immune system, which possess powerful antitumor activity. NK cells exhibit their function through a complex collection of receptors that act synergistically to recognize, regulate, or amplify the immune response. TLRs allow cells to detect PAMPs, MAMPs, or DAMPs, which are essential for the initiation of the immune response. Studies on the different subpopulations of NK cells and their expression profile of innate immune receptors in hematological cancers are limited. In this study, the specific subpopulations of NK cells in pediatric patients with acute lymphoblastic leukemia (ALL) and the repertoire and level of expression of TLRs in cytotoxic NK cells were assessed. The results suggested that pediatric patients with ALL exhibited a significant decrease in NK cells in peripheral blood and bone marrow, in addition to alterations in the distribution of the subpopulations of cells. Regulatory and cytotoxic NK cells were diminished, whereas dysfunctional phenotype was considerably increased. Cytotoxic NK cells from children with ALL expressed all 10 TLRs, and expression of TLR1 and TLR9 was decreased compared with the controls. Interestingly, cytotoxic NK cells exhibited a higher expression of TLR1 in the bone marrow than in the peripheral blood of patients with ALL. The present study is the first to show that TLR10 was expressed in the cytotoxic NK cells and the first to assess the profile and levels of the 10 known TLRs in cytotoxic NK cells from patients with ALL. The alterations in expression levels and cellular distribution may be involved in the immune response.