RESUMO
The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph-) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL.
Assuntos
Isocitrato Desidrogenase/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Adolescente , Adulto , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Criança , Humanos , Isocitrato Desidrogenase/metabolismo , Pessoa de Meia-Idade , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Transcriptoma , Adulto JovemRESUMO
The canonical Wnt/ß-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling ß-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/ß-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.
Assuntos
Autorrenovação Celular , Intestinos/citologia , Receptores Acoplados a Proteínas G/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Trombospondinas/metabolismo , Proteínas Wnt/metabolismo , Animais , Linhagem da Célula , Proliferação de Células , Feminino , Humanos , Ligantes , Masculino , Camundongos , Organoides/citologia , Organoides/crescimento & desenvolvimento , Análise de Célula Única , Nicho de Células-Tronco , Transcriptoma , Ubiquitina-Proteína Ligases/metabolismo , beta Catenina/metabolismoRESUMO
Neuroblastoma (NB) and pheochromocytoma (PCC) are derived from neural crest cells (NCCs); however, composite tumors with NB and PCC are rare, and their underlying molecular mechanisms remain unknown. To address this issue, we performed exome and transcriptome sequencing with formalin-fixed paraffin-embedded (FFPE) samples from the NB, PCC, and mixed lesions in a patient with a composite tumor. Whole-exome sequencing revealed that most mutations (80%) were shared by all samples, indicating that NB and PCC evolved from the same clone. Notably, all samples harbored both mutation and focal amplification in the FGFR1 oncogene, resulting in an extraordinarily high expression, likely to be the main driver of this tumor. Transcriptome sequencing revealed undifferentiated expression profiles for the NB lesions. Considering that a metastatic lesion was also composite, most likely, the primitive founding lesions should differentiate into both NB and PCC. This is the first reported case with composite-NB and PCC genetically proven to harbor an oncogenic FGFR1 alteration of a common cellular origin.
Assuntos
Neoplasias das Glândulas Suprarrenais , Neuroblastoma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Humanos , Mutação , Neuroblastoma/genética , Neuroblastoma/patologia , Oncogenes , Feocromocitoma/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
A lack of practical resources in Japan has limited preclinical discovery and testing of therapies for pediatric relapsed and refractory acute lymphoblastic leukemia (ALL), which has poor outcomes. Here, we established 57 patient-derived xenografts (PDXs) in NOD.Cg-Prkdcscid ll2rgtm1Sug /ShiJic (NOG) mice and created a biobank by preserving PDX cells including three extramedullary relapsed ALL PDXs. We demonstrated that our PDX mice and PDX cells mimicked the biological features of relapsed ALL and that PDX models reproduced treatment-mediated clonal selection. Our PDX biobank is a useful scientific resource for capturing drug sensitivity features of pediatric patients with ALL, providing an essential tool for the development of targeted therapies.
Assuntos
Bancos de Espécimes Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Camundongos , Animais , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos NOD , Japão , Xenoenxertos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Camundongos SCID , Modelos Animais de DoençasRESUMO
Lineage switch is a rare event at leukemic relapse. While mostly known to occur in KMT2A-rearranged infant leukemia, the underlying mechanism is yet to be depicted. This case report describes a female infant who achieved remission of KMT2A-MLLT3-rearranged acute monocytic leukemia, but 6 months thereafter, relapsed as KMT2A-MLLT3-rearranged acute lymphocytic leukemia. Whole exome sequencing of the bone marrow obtained pre-post lineage switch revealed two somatic mutations of PAX5 in the relapse sample. These two PAX5 alterations were suggested to be loss of function, thus to have played the driver role in the lineage switch from acute monocytic leukemia to acute lymphocytic leukemia.
Assuntos
Leucemia Monocítica Aguda , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Medula Óssea , Criança , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Leucemia Monocítica Aguda/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Fator de Transcrição PAX5 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RecidivaRESUMO
Due to the considerable success of cancer immunotherapy for leukemia, the tumor immune environment has become a focus of intense research; however, there are few reports on the dynamics of the tumor immune environment in leukemia. Here, we analyzed the tumor immune environment in pediatric B cell precursor acute lymphoblastic leukemia by analyzing serial bone marrow samples from nine patients with primary and recurrent disease by mass cytometry using 39 immunophenotype markers, and transcriptome analysis. High-dimensional single-cell mass cytometry analysis elucidated a dynamic shift of T cells from naïve to effector subsets, and clarified that, during relapse, the tumor immune environment comprised a T helper 1-polarized immune profile, together with an increased number of effector regulatory T cells. These results were confirmed in a validation cohort using conventional flow cytometry. Furthermore, RNA transcriptome analysis identified the upregulation of immune-related pathways in B cell precursor acute lymphoblastic leukemia cells during relapse, suggesting interaction with the surrounding environment. In conclusion, a tumor immune environment characterized by a T helper 1-polarized immune profile, with an increased number of effector regulatory T cells, could contribute to the pathophysiology of recurrent B cell precursor acute lymphoblastic leukemia. This information could contribute to the development of effective immunotherapeutic approaches against B cell precursor acute lymphoblastic leukemia relapse.
Assuntos
Biomarcadores Tumorais/genética , Medula Óssea/imunologia , Perfilação da Expressão Gênica/métodos , Recidiva Local de Neoplasia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Medula Óssea/química , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Microambiente Tumoral , Regulação para Cima , Adulto JovemRESUMO
BACKGROUND: KLF5 plays a crucial role in stem cells of colorectum in cooperation with Lgr5 gene. In this study, we aimed to explicate a regulatory mechanism of the KLF5 gene product from a view of three-dimensional genome structure in colorectal cancer (CRC). METHODS: In vitro engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP)-seq method was used to identify the regions that bind to the KLF5 promoter. RESULTS: We revealed that the KLF5 promoter region interacted with the KLF5 enhancer region as well as the transcription start site (TSS) region of the Colon Cancer Associated Transcript 1 (CCAT1) gene. Notably, the heterodeletion mutants of KLF5 enhancer impaired the cancer stem-like properties of CRC cells. The KLF5 protein participated in the core-regulatory circuitry together with co-factors (BRD4, MED1, and RAD21), which constructs the three-dimensional genome structures consisting of KLF5 promoter, enhancer and CCAT1 TSS region. In vitro analysis indicated that KLF5 regulated CCAT1 expression and we found that CCAT1 expression was highly correlated with KLF5 expression in CRC clinical samples. CONCLUSIONS: Our data propose the mechanistic insight that the KLF5 protein constructs the core-regulatory circuitry with co-factors in the three-dimensional genome structure and coordinately regulates KLF5 and CCAT1 expression in CRC.
Assuntos
Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/metabolismo , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Células-Tronco/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Taxa de SobrevidaRESUMO
Approximately 20% of patients with transient abnormal myelopoiesis (TAM) die due to hepatic or multiorgan failure. To identify potential new treatments for TAM, we performed in vitro drug sensitivity testing (DST) using the peripheral blood samples of eight patients with TAM. DST screened 41 agents for cytotoxic properties against TAM blasts. Compared with the reference samples of healthy subjects, TAM blasts were more sensitive to glucocorticoids, the mitogen-activated protein kinase kinase (MAP2K) inhibitor trametinib, and cytarabine. Our present results support the therapeutic potential of glucocorticoids and the role of the RAS/MAP2K signalling pathway in TAM pathogenesis.
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Reação Leucemoide/tratamento farmacológico , Mielopoese/efeitos dos fármacos , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores , Técnicas de Cultura de Células , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Ensaios de Triagem em Larga Escala , Humanos , Imuno-Histoquímica , Reação Leucemoide/etiologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-IdadeRESUMO
Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole-exome sequencing identified extensive copy-neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes.
Assuntos
Mutação em Linhagem Germinativa , Perda de Heterozigosidade , Neoplasias Primárias Múltiplas/genética , Neuroblastoma/genética , Neoplasias Ovarianas/genética , Teratoma/genética , Adolescente , Proteínas F-Box/genética , Feminino , Homozigoto , Humanos , Neoplasias Primárias Múltiplas/tratamento farmacológico , Neoplasias Primárias Múltiplas/patologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Proteína p130 Retinoblastoma-Like/genética , Teratoma/tratamento farmacológico , Teratoma/patologia , Sequenciamento do ExomaRESUMO
Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to arise from neural crest-derived immature cells. The prognosis of patients with high-risk or recurrent/refractory neuroblastoma remains quite poor despite intensive multimodality therapy; therefore, novel therapeutic interventions are required. We examined the expression of a cell adhesion molecule CD146 (melanoma cell adhesion molecule [MCAM]) by neuroblastoma cell lines and in clinical samples and investigated the anti-tumor effects of CD146-targeting treatment for neuroblastoma cells both in vitro and in vivo. CD146 is expressed by 4 cell lines and by most of primary tumors at any stage. Short hairpin RNA-mediated knockdown of CD146, or treatment with an anti-CD146 polyclonal antibody, effectively inhibited growth of neuroblastoma cells both in vitro and in vivo, principally due to increased apoptosis via the focal adhesion kinase and/or nuclear factor-kappa B signaling pathway. Furthermore, the anti-CD146 polyclonal antibody markedly inhibited tumor growth in immunodeficient mice inoculated with primary neuroblastoma cells. In conclusion, CD146 represents a promising therapeutic target for neuroblastoma.
Assuntos
Anticorpos/uso terapêutico , Antígeno CD146/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Neuroblastoma/terapia , RNA Interferente Pequeno/uso terapêutico , Animais , Apoptose , Antígeno CD146/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Quinase 1 de Adesão Focal/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos , NF-kappa B/metabolismo , Recidiva Local de Neoplasia , Transplante de Neoplasias , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Prognóstico , Transdução de Sinais , Esferoides Celulares , Transdução Genética/métodosRESUMO
Previous genomic studies have revealed the genomic landscape of myeloma cells. Although some of the genomic abnormalities shown are believed to be correlated to the molecular pathogenesis of multiple myeloma and/or clinical outcome, these correlations are not fully understood. The aim of this study is to elucidate the correlation between genomic abnormalities and clinical characteristics by targeted capture sequencing in the Japanese multiple myeloma cohort. We analysed 154 patients with newly diagnosed multiple myeloma. The analysis revealed that the study cohort consisted of a less frequent hyperdiploid subtype (37·0%) with relatively high frequencies of KRAS mutation (36·4%) and IGH-CCND1 translocation (26·6%) compared with previous reports. Moreover, our targeted capture sequencing strategy was able to detect rare IGH-associated chromosomal translocations, such as IGH-CCND2 and IGH-MAFA. Interestingly, all 10 patients harboured MAX mutations accompanied by 14q23 deletion. The patients with del(17p) exhibited an unfavourable clinical outcome, and the presence of KRAS mutation was associated with shorter survival in patients with multiple myeloma, harbouring IGH-CCND1. Thus, our study provides a detailed landscape of genomic abnormalities, which may have potential clinical application for patients with multiple myeloma.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Mieloma Múltiplo/genética , Proteínas de Neoplasias/genética , Síndrome de Smith-Magenis/genética , Adulto , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Owing to recent technological advancements, using next-generation sequencing (NGS) and the accumulation of clinical experiences worldwide, more than 420 genes associated with inborn errors of immunity (IEI) have been identified, which exhibit large genotypic and phenotypic variations. Consequently, NGS-based comprehensive genetic analysis, including whole-exome sequencing (WES), have become more valuable in the clinical setting and have contributed to earlier diagnosis, improved treatment, and prognosis. However, these approaches have the following disadvantages that need to be considered: a relatively low diagnostic rate, high cost, difficulties in the interpretation of each variant, and the risk of incidental findings. Thus, the objective of this study is to review our WES results of a large number of patients with IEI and to elucidate patient characteristics, which are related to the positive WES result. METHODS: We performed WES for 136 IEI patients with negative conventional screening results for candidate genes and classified these variants depending on validity of their pathogenicity. RESULTS: We identified disease-causing pathogenic mutations in 36 (26.5%) of the patients which were found in known IEI-causing genes. Although the overall diagnostic rate was not high and was not apparently correlated with the clinical subcategories and severity, we revealed that earlier onset with longer duration of diseases were associated with positive WES results, especially in pediatric cases. CONCLUSIONS: Most of the disease-causing germline mutations were located in the known IEI genes which could be predicted using patients' clinical characteristics. These results may be useful when considering appropriate genetic approaches in the clinical setting.
Assuntos
Genótipo , Mutação em Linhagem Germinativa/genética , Imunidade/genética , Mutação/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Doenças Genéticas Inatas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Sequenciamento do Exoma , Adulto JovemRESUMO
Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur after treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the development of tMNs following ASCT at the molecular level by whole-exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMNs as compared with de novo myelodysplastic syndrome (MDS) (median 27 vs 12 mutations; P = .001). The mutations found in tMNs did not carry a clear aging-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMNs and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. By use of TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the patients with tMNs. Reconstruction of clonal patterns based on VAFs revealed that premalignant clones can be present more than 7 years preceding a tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development after ASCT originates in HSCs bearing (pre-)tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of premalignant clones and monitoring of their evolutionary trajectory may help to predict the development of tMNs and guide early intervention in the future.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Transtornos Mieloproliferativos , Segunda Neoplasia Primária , Adulto , Idoso , Autoenxertos , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/terapia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/genética , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/genética , Estudos RetrospectivosRESUMO
Genetic alterations, including mutations and copy-number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic stem cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy-number alterations, whose effects on transplantation outcomes were investigated. We identified 1776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival; clinical characteristics accounted for 70% of risk. TP53 and RAS-pathway mutations, together with complex karyotype (CK) as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected posttransplant survival independently of clinical factors. Regardless of disease subtype, TP53-mutated patients with CK were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better in TP53-mutated patients without CK. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Our results suggest that TP53 and RAS-pathway mutations predicted a dismal prognosis, when associated with CK and MDS/MPNs, respectively. However, for patients with mutated TP53 or CK alone, long-term survival could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.
Assuntos
Aberrações Cromossômicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteína Supressora de Tumor p53/genética , Proteínas ras/genética , Adolescente , Adulto , Idoso , Criança , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Risco , Transplante Homólogo , Resultado do Tratamento , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/metabolismoRESUMO
The authors report two siblings with familial neuroblastoma with a germline R1275Q mutation of the tyrosine kinase domain of ALK. Whole exome sequencing and copy number variation assay were performed to investigate genetic alterations in the two cases. No common somatic mutations or gene polymorphisms related to the tumorigenesis of neuroblastoma were detected. A distinct pattern involving both segmental chromosomal alteration and MYCN amplification was detected. The diversity of biological behavior of familial neuroblastoma harboring a germline ALK mutation may depend on conventional prognostic factors, such as segmental chromosomal alterations and MYCN amplification, rather than additional acquired mutations.
Assuntos
Quinase do Linfoma Anaplásico/genética , Mutação em Linhagem Germinativa , Neoplasias Primárias Múltiplas/genética , Neuroblastoma/genética , Neoplasias das Glândulas Suprarrenais/genética , Pré-Escolar , Exoma , Feminino , Humanos , Lactente , Neoplasias Hepáticas/genética , Masculino , Neoplasias do Mediastino/genética , Linhagem , Fenótipo , Mutação Puntual , Neoplasias da Coluna Vertebral/genéticaRESUMO
Autoimmune diseases in children are rare and can be difficult to diagnose. Single causative genes have been identified for some pediatric autoimmune diseases. Such orphan diseases may not be diagnosed properly due to the variability of patients' phenotypes. Guidelines for the diagnostic process need to be developed. Fifteen patients with uncharacterized childhood autoimmune diseases with lymphoproliferation that had negative testing for autoimmune lymphoproliferative syndrome were subjected to whole-exome sequencing to identify genes associated with these conditions. Five causative genes, CTLA4, STAT3, TNFAIP3, IKZF1, and PSTPIP1, were identified. These genes should be considered as candidates for uncharacterized childhood autoimmune diseases with lymphoproliferation.
Assuntos
Doenças Autoimunes/genética , Transtornos Linfoproliferativos/genética , Proteínas de Neoplasias/genética , Adolescente , Doenças Autoimunes/complicações , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Transtornos Linfoproliferativos/complicações , MasculinoRESUMO
BACKGROUND: Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well-characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS-dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS-like phenotype. OBJECTIVE: The aim of the present study was to elucidate the genetic cause of the ALPS-like phenotype. METHODS: Candidate genes associated with the ALPS-like phenotype were screened by using whole-exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. RESULTS: A de novo heterozygous frameshift mutation of TNF-α-induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor κB pathway, was identified in one of the patients exhibiting the ALPS-like phenotype. Increased activity of the nuclear factor κB pathway was associated with haploinsufficiency of TNFAIP3 (A20). CONCLUSION: Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.
Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Síndrome Linfoproliferativa Autoimune/imunologia , Células Cultivadas , Mutação em Linhagem Germinativa , Haploinsuficiência , Humanos , Lactente , Leucócitos Mononucleares/imunologia , Masculino , NF-kappa B/imunologia , Fenótipo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Ikaros, which is encoded by IKZF1, is a transcriptional factor that play a critical role in hematopoiesis. Somatic IKZF1 alterations are known to be involved in the pathogenesis of leukemia in human subjects. Recently, immunodeficiency caused by germline IKZF1 mutation has been described. OBJECTIVE: We sought to describe the clinical and immunologic phenotypes of Japanese patients with heterozygous IKZF1 mutations. METHODS: We performed whole-exome sequencing in patients from a dysgammaglobulinemia or autoimmune disease cohort and used a candidate gene approach in 4 patients. Functional and laboratory studies, including detailed lymphopoiesis/hematopoiesis analysis in the bone marrow, were performed. RESULTS: Nine patients from 6 unrelated families were identified to have heterozygous germline mutations in IKZF1. Age of onset was 0 to 20 years (mean, 7.4 years). Eight of 9 patients presented with dysgammaglobulinemia accompanied by B-cell deficiency. Four of 9 patients had autoimmune disease, including immune thrombocytopenic purpura, IgA vasculitis, and systemic lupus erythematosus. Nonautoimmune pancytopenia was observed in 1 patient. All of the mutant Ikaros protein demonstrated impaired DNA binding to the target sequence and abnormal diffuse nuclear localization. Flow cytometric analysis of bone marrow revealed reduced levels of common lymphoid progenitors and normal development of pro-B to pre-B cells. CONCLUSIONS: Germline heterozygous IKZF1 mutations cause dysgammaglobulinemia; hematologic abnormalities, including B-cell defect; and autoimmune diseases.
Assuntos
Doenças Autoimunes/genética , Doenças Hematológicas/genética , Fator de Transcrição Ikaros/genética , Adolescente , Adulto , Doenças Autoimunes/imunologia , Autoimunidade , Linfócitos B/imunologia , Criança , Feminino , Mutação em Linhagem Germinativa , Doenças Hematológicas/imunologia , Hematopoese/genética , Humanos , Fator de Transcrição Ikaros/imunologia , Contagem de Linfócitos , Masculino , Linfócitos T/imunologia , Adulto JovemRESUMO
The regrowth of amputated limbs and the distal tips of digits represent models of tissue regeneration in amphibians, fish and mice. For decades it had been assumed that limb regeneration derived from the blastema, an undifferentiated pluripotent cell population thought to be derived from mature cells via dedifferentiation. Here we show that a wide range of tissue stem/progenitor cells contribute towards the restoration of the mouse distal digit. Genetic fate mapping and clonal analysis of individual cells revealed that these stem cells are lineage restricted, mimicking digit growth during development. Transplantation of cyan-fluorescent-protein-expressing haematopoietic stem cells, and parabiosis between genetically marked mice, confirmed that the stem/progenitor cells are tissue resident, including the cells involved in angiogenesis. These results, combined with those from appendage regeneration in other vertebrate subphyla, collectively demonstrate that tissue stem cells rather than pluripotent blastema cells are an evolutionarily conserved cellular mode for limb regeneration after amputation.
Assuntos
Linhagem da Célula , Extremidades/crescimento & desenvolvimento , Camadas Germinativas/citologia , Regeneração/fisiologia , Células-Tronco/citologia , Animais , Osso e Ossos/citologia , Células Clonais , Ectoderma/citologia , Ectoderma/crescimento & desenvolvimento , Endotélio/citologia , Endotélio/crescimento & desenvolvimento , Feminino , Células-Tronco Hematopoéticas/citologia , Masculino , Mesoderma/citologia , Mesoderma/crescimento & desenvolvimento , Camundongos , Especificidade de Órgãos , Tendões/citologia , Tendões/crescimento & desenvolvimentoRESUMO
Intracranial germ cell tumor is sometimes associated with Down syndrome; however, no optimal treatment has been developed due to the high risk of recurrence and treatment-related mortality. Here, we report on a patient with an intracranial germinoma in the bilateral basal ganglia. The patient received 3 courses of ifosfamide-cisplatin-etoposide in combination with whole-brain irradiation (24 Gy), with no serious complications. The patient is alive and disease free 16 months after the initial diagnosis. This regimen is a feasible treatment for intracranial germ cell tumor associated with Down syndrome, although careful attention must be paid to the increased risk for severe infection.