RESUMEN
Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.
Asunto(s)
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Niño , Humanos , Estudio de Asociación del Genoma Completo , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Factores de Transcripción/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genéticaAsunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Japón/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido SimpleRESUMEN
Noonan syndrome-related myeloproliferative disorder (NS/MPD) and juvenile myelomonocytic leukemia (JMML) are rare MPDs that occur in young children. We herein report a case of NS/MPD with neonatal onset. The patient had a characteristic appearance and high monocyte count in the peripheral blood and bone marrow. Genetic testing showed the E139D mutation in PTPN11 ; however, the patient did not meet all the diagnostic criteria for JMML, and we thus diagnosed him with NS/MPD. Eight other cases of NS/MPD with neonatal onset are also summarized. The initial presentation varied, and the prognosis was considered poor compared with previous reports of NS/MPD.
Asunto(s)
Leucemia Mielomonocítica Juvenil , Trastornos Mieloproliferativos , Síndrome de Noonan , Humanos , Recién Nacido , Masculino , Leucemia Mielomonocítica Juvenil/complicaciones , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/genética , Mutación , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/genética , Síndrome de Noonan/complicaciones , Síndrome de Noonan/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genéticaRESUMEN
Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.
Asunto(s)
Asparaginasa , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/terapia , Enfermedad Aguda , Células Asesinas Naturales , Resultado del Tratamiento , Proteínas Represoras , Proteínas Supresoras de TumorAsunto(s)
Hepatopatías , Deficiencia de Proteína C , Trombofilia , Trombosis de la Vena , Humanos , Deficiencia de Proteína C/complicaciones , Deficiencia de Proteína C/diagnóstico , Deficiencia de Proteína C/genética , Vena Porta , Trombosis de la Vena/complicaciones , Trombosis de la Vena/diagnósticoRESUMEN
Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110δ (responsible gene: PIK3CD) was described in 2013. The disease is characterized by recurrent airway infections and bronchiectasis. It is associated with hyper-IgM syndrome due to the defect of immunoglobulin class switch recombination and decreased CD27-positive memory B cells. Patients also suffered from immune dysregulations, such as lymphadenopathy, autoimmune cytopenia or enteropathy. T-cell dysfunction due to increased senescence is associated with a decrease in CD4-positive T lymphocytes and CD45RA-positive naive T lymphocytes, along with increased susceptibility to Epstein-Barr virus/cytomegalovirus infections. In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF), APDS2 (PIK3R1-LOF) and APDS-L (PTEN-LOF). Since the pathophysiology of patients with APDS varies with a wide range of severity, it is crucial that patients receive appropriate treatment and management. Our research group created a disease outline and a diagnostic flow chart and summarized clinical information such as the severity classification of APDS and treatment options.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Síndromes de Inmunodeficiencia , Humanos , Síndromes de Inmunodeficiencia/genética , Fosfatidilinositol 3-Quinasa/uso terapéutico , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/uso terapéutico , Japón , Herpesvirus Humano 4 , Fosfatidilinositoles/uso terapéuticoRESUMEN
Common variable immunodeficiency (CVID) causes granulomatous-lymphocytic interstitial lung disease (GLILD) and has a poor prognosis. We herein report a case of GLILD in a 49-year-old woman with CTLA-4 deficiency-associated CVID. The patient presented with dyspnea that had worsened over the past two years. A laboratory examination revealed hypoglobulinemia and pancytopenia. Chest computed tomography showed diffuse infiltrative and granular shadows in the bilateral interstitium. A flow cytometric analysis of blood cells and genetic testing confirmed CTLA-4 deficiency. We performed video-assisted thoracoscopic surgery for the pathological diagnosis of GLILD and to exclude infection and malignancy. Corticosteroid treatment successfully improved the condition of the patient.
Asunto(s)
Inmunodeficiencia Variable Común , Enfermedades Pulmonares Intersticiales , Femenino , Humanos , Persona de Mediana Edad , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Antígeno CTLA-4 , Granuloma/diagnóstico , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/tratamiento farmacológico , Inmunodeficiencia Variable Común/diagnóstico , Tomografía Computarizada por Rayos X/efectos adversosAsunto(s)
Mutación con Ganancia de Función , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Péptidos y Proteínas de Señalización Intracelular/genética , Fenotipo , Adolescente , Biomarcadores , Niño , Preescolar , Estudios de Asociación Genética/métodos , Humanos , Inmunofenotipificación , Lactante , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
The Primary Immunodeficiency Database in Japan (PIDJ) is a registry of primary immunodeficiency diseases (PIDs) that was established in 2007. The database is a joint research project with research groups associated with the Ministry of Health, Labor and Welfare; the RIKEN Research Center for Allergy and Immunology (RCAI); and the Kazusa DNA Research Institute (KDRI). The PIDJ contains patient details, including the age, sex, clinical and laboratory findings, types of infections, genetic analysis results, and treatments administered. In addition, web-based case consultation is also provided. The PIDJ serves as a database for patients with PIDs and as a patient consultation service connecting general physicians with PID specialists and specialized hospitals. Thus, the database contributes to investigations related to disease pathogenesis and the early diagnosis and treatment of patients with PIDs. In the 9 years since the launch of PIDJ, 4,481 patients have been enrolled, of whom 64% have been subjected to genetic analysis. In 2017, the Japanese Society for Immunodeficiency and Autoinflammatory Diseases (JSIAD) was established to advance the diagnosis, treatment, and research in the field of PIDs and autoinflammatory diseases (AIDs). JSIAD promotes the analysis of the pathogenesis of PIDs and AIDs, enabling improved patient care and networking via the expansion of the database and construction of a biobank obtained from the PIDJ. The PIDJ was upgraded to "PIDJ ver.2" in 2019 by JSIAD. Currently, PIDJ ver.2 is used as a platform for epidemiological studies, genetic analysis, and pathogenesis evaluation for PIDs and AIDs.
Asunto(s)
Bases de Datos Factuales/estadística & datos numéricos , Diagnóstico Precoz , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/terapia , Sistema de Registros/estadística & datos numéricos , Femenino , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Humanos , Japón , Masculino , Enfermedades de Inmunodeficiencia Primaria/genéticaRESUMEN
IKAROS and CTLA4 deficiencies are inborn errors of immunity and show similar clinical phenotypes, including hypogammaglobulinemia and autoimmune diseases (ADs). However, the differences in clinical features and pathogenesis of these are not fully understood. Therefore, we performed systematic literature reviews for IKAROS and CTLA4 deficiencies. The reviews suggested that patients with IKAROS deficiency develop AD earlier than hypogammaglobulinemia. However, no study assessed the detailed changes in clinical manifestations over time; this was likely due to the cross-sectional nature of the studies. Therefore, we conducted a retrospective longitudinal study on IKAROS and CTLA4 deficiencies in our cohort to evaluate the clinical course over time. In patients with IKAROS deficiency, AD and hypogammaglobulinemia often develop in that order, and AD often resolves before the onset of hypogammaglobulinemia; these observations were not found in patients with CTLA4 deficiency. Understanding this difference in the clinical course helps in the clinical management of both. Furthermore, our results suggest B- and T-cell-mediated ADs in patients with IKAROS and CTLA4 deficiencies, respectively.
Asunto(s)
Antígeno CTLA-4/deficiencia , Factor de Transcripción Ikaros/deficiencia , Errores Innatos del Metabolismo , Enfermedades Autoinmunes , Humanos , Estudios Longitudinales , Enfermedades de Inmunodeficiencia Primaria , Estudios RetrospectivosRESUMEN
BACKGROUND: Microcephalic osteodysplastic primordial dwarfism type I (MOPD I, also known as Taybi-Linder syndrome) is a rare genetic disorder associated with severe intrauterine growth retardation, short stature, microcephaly, brain anomalies, stunted limbs, and early mortality. RNU4ATAC, the gene responsible for this disorder, does not encode a protein but instead the U4atac small nuclear RNA (snRNA), a crucial component of the minor spliceosome. Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications. CASE REPORT: The patient described herein is an 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at the age of one, thereafter resulting in severe psychomotor disabilities. Genetic analysis using gene microarray and whole-exome sequencing could not identify the cause of her congenital anomalies. However, Sanger sequencing revealed a compound heterozygous mutation within RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity. Furthermore, antibodies against varicella-zoster, rubella, measles, mumps, and influenza were very low or negative despite having received vaccinations for these viruses. HHV-6 IgG antibodies were also undetected. DISCUSSION: The patient here exhibited a marked MOPD I phenotype complicated by various immunodeficiencies. Previous studies have not demonstrated immunodeficiency comorbidities within MOPD I subjects, but this report suggests an evident immunodeficiency in MOPD I. Patients with MOPD I should be treated with one of the immunodeficiency syndromes.
Asunto(s)
Cardiomiopatías/genética , Enanismo/genética , Retardo del Crecimiento Fetal/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Enfermedades de Inmunodeficiencia Primaria/genética , ARN Nuclear Pequeño/genética , Enfermedades de la Retina/genética , Adolescente , Alelos , Cardiomiopatías/fisiopatología , Enanismo/fisiopatología , Femenino , Retardo del Crecimiento Fetal/fisiopatología , Humanos , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Microcefalia/fisiopatología , Mutación , Osteocondrodisplasias/fisiopatología , Linaje , Fenotipo , Enfermedades de Inmunodeficiencia Primaria/fisiopatología , Enfermedades de la Retina/fisiopatología , Secuenciación del ExomaRESUMEN
BACKGROUND: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. OBJECTIVE: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. METHODS: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. RESULTS: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. CONCLUSION: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Síndromes de Inmunodeficiencia , Trastornos Linfoproliferativos , Adolescente , Adulto , Aloinjertos , Niño , Preescolar , Fosfatidilinositol 3-Quinasa Clase I/inmunología , Supervivencia sin Enfermedad , Femenino , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/mortalidad , Síndromes de Inmunodeficiencia/patología , Síndromes de Inmunodeficiencia/terapia , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/terapia , Masculino , Enfermedades de Inmunodeficiencia Primaria , Tasa de SupervivenciaRESUMEN
Genome-wide association studies (GWAS) performed mostly in populations of European and Hispanic ancestry have confirmed an inherited genetic basis for childhood acute lymphoblastic leukemia (ALL), but these associations are less clear in other races/ethnicities. DNA samples from ALL patients (aged 0-19 years) previously enrolled onto a Tokyo Children's Cancer Study Group trial were collected during 2013-2015, and underwent single nucleotide polymorphism (SNP) microarray genotyping resulting in 527 B-cell ALL for analysis. Cases and control data for 3,882 samples from the Nagahama Study Group and Aichi Cancer Center Study were combined, and association analyses across 10 previous GWAS-identified regions were performed after targeted SNP imputation. Linkage disequilibrium (LD) patterns in Japanese and other populations were evaluated using the varLD score based on 1000 Genomes data. Risk associations for ARID5B (rs10821936, OR = 1.84, P = 6 × 10-17) and PIP4K2A (rs7088318, OR = 0.76, P = 2 × 10-4) directly transferred to Japanese, and the IKZF1 association was detected by an alternate SNP (rs1451367, OR = 1.52, P = 2 × 10-6). Marked regional LD differences between Japanese and Europeans was observed for most of the remaining loci for which associations did not transfer, including CEBPE, CDKN2A, CDKN2B, and ELK3. This study represents a first step towards characterizing the role of genetic susceptibility in childhood ALL risk in Japanese.
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Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adolescente , Niño , Preescolar , Proteínas de Unión al ADN/genética , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Factor de Transcripción Ikaros/genética , Lactante , Recién Nacido , Japón , Desequilibrio de Ligamiento , Masculino , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción/genética , Adulto JovenAsunto(s)
Proteínas Hedgehog/genética , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Megacarioblástica Aguda/genética , Proteínas de Fusión Oncogénica/genética , Proteínas ras/genética , Biomarcadores de Tumor , Niño , Terapia Combinada , Humanos , Leucemia Megacarioblástica Aguda/terapia , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Recurrencia , Resultado del TratamientoRESUMEN
Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4+ T cells were skewed toward CD45RO+ memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.
Asunto(s)
Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Adolescente , Adulto , Biomarcadores , Niño , Preescolar , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/terapia , Análisis Mutacional de ADN , Diagnóstico Diferencial , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Anemia de Fanconi/inmunología , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , Femenino , Citometría de Flujo , Humanos , Lactante , Masculino , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Secuenciación del Exoma , Adulto JovenRESUMEN
Patients with mutations in AICDA, which encodes activation-induced cytidine deaminase (AID), display an impaired peripheral B cell tolerance. AID mediates class-switch recombination (CSR) and somatic hypermutation (SHM) in B cells, but the mechanism by which AID prevents the accumulation of autoreactive B cells in blood is unclear. Here, we analyzed B cell tolerance in AID-deficient patients, patients with autosomal dominant AID mutations (AD-AID), asymptomatic AICDA heterozygotes (AID+/-), and patients with uracil N-glycosylase (UNG) deficiency, which impairs CSR but not SHM. The low frequency of autoreactive mature naive B cells in UNG-deficient patients resembled that of healthy subjects, revealing that impaired CSR does not interfere with the peripheral B cell tolerance checkpoint. In contrast, we observed decreased frequencies of SHM in memory B cells from AD-AID patients and AID+/- subjects, who were unable to prevent the accumulation of autoreactive mature naive B cells. In addition, the individuals with AICDA mutations, but not UNG-deficient patients, displayed Tregs with defective suppressive capacity that correlated with increases in circulating T follicular helper cells and enhanced cytokine production. We conclude that SHM, but not CSR, regulates peripheral B cell tolerance through the production of mutated antibodies that clear antigens and prevent sustained interleukin secretions that interfere with Treg function.
Asunto(s)
Linfocitos B/inmunología , Puntos de Control del Ciclo Celular/inmunología , Citidina Desaminasa/deficiencia , Tolerancia Inmunológica , Memoria Inmunológica , Mutación , Hipermutación Somática de Inmunoglobulina/inmunología , Linfocitos B/patología , Puntos de Control del Ciclo Celular/genética , Citidina Desaminasa/inmunología , Femenino , Humanos , Masculino , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patologíaRESUMEN
BACKGROUND: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6. OBJECTIVE: This study aimed to identify novel genes responsible for APDS. METHODS: Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays. RESULTS: We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway. CONCLUSION: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , Síndromes de Inmunodeficiencia/genética , Linfocitos/inmunología , Mutación/genética , Fosfohidrolasa PTEN/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Linaje , Fosforilación , Enfermedades de Inmunodeficiencia Primaria , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Tensinas/metabolismoRESUMEN
The complication of Fanconi anemia (FA) with acute leukemia is rare and challenging to treat because of high relapse rates, despite the improved outcome of hematopoietic stem cell transplantation with fludarabine-based conditioning for treating FA patients with hematological abnormalities. We added high-dose cytarabine to fludarabine-based conditioning to promote an enhanced antitumor effect and successfully subjected 4 patients with FA, including 3 with acute leukemia, to hematopoietic stem cell transplantation. All patients remain alive without treatment-related mortality or evidence of disease. Adding high-dose cytarabine to fludarabine-based conditioning may be tolerable and effective for treating FA patients with acute leukemia.