Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
2.
Curr Treat Options Oncol ; 23(4): 543-561, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35294722

RESUMO

OPINION STATEMENT: Acute lymphoblastic leukemia (ALL) is the most frequent type of pediatric cancer with a peak incidence at 2-5 years of age. ALL frequently begins in utero with the emergence of clinically silent, preleukemic cells. Underlying leukemia-predisposing germline and acquired somatic mutations define distinct ALL subtypes that vary dramatically in treatment outcomes. In addition to genetic predisposition, a second hit, which usually occurs postnatally, is required for development of overt leukemia in most ALL subtypes. An untrained, dysregulated immune response, possibly due to an abnormal response to infection, may be an important co-factor triggering the onset of leukemia. Furthermore, the involvement of natural killer (NK) cells and T helper (Th) cells in controlling the preleukemic cells has been discussed. Identifying the cell of origin of the preleukemia-initiating event might give additional insights into potential options for prevention. Modulation of the immune system to achieve prolonged immunosurveillance of the preleukemic clone that eventually dies out in later years might present a future directive. Herein, we review the concepts of prenatal origin as well as potential preventive approaches to pediatric B cell precursor (BCP) ALL.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Predisposição Genética para Doença , Humanos , Monitorização Imunológica , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
3.
Methods Mol Biol ; 2185: 113-134, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33165846

RESUMO

Recurrent chromosomal translocations define genetic subtypes of childhood leukemia and present the first hit that generates an expanded clone of preleukemic cells in the bone marrow. Most commonly, reverse transcriptase PCR is used to detect these translocations on RNA level. This technique has severe drawbacks, including sensitivity to contamination and instability of RNA. Here, we describe the genomic inverse PCR for exploration of ligated breakpoints (GIPFEL) that overcomes these pitfalls.


Assuntos
Células da Medula Óssea , Leucemia , Lesões Pré-Cancerosas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Humanos , Recém-Nascido , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Masculino , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia
4.
Blood ; 136(18): 2003-2017, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-32911536

RESUMO

The majority of childhood leukemias are precursor B-cell acute lymphoblastic leukemias (pB-ALLs) caused by a combination of prenatal genetic predispositions and oncogenic events occurring after birth. Although genetic predispositions are frequent in children (>1% to 5%), fewer than 1% of genetically predisposed carriers will develop pB-ALL. Although infectious stimuli are believed to play a major role in leukemogenesis, the critical determinants are not well defined. Here, by using murine models of pB-ALL, we show that microbiome disturbances incurred by antibiotic treatment early in life were sufficient to induce leukemia in genetically predisposed mice, even in the absence of infectious stimuli and independent of T cells. By using V4 and full-length 16S ribosomal RNA sequencing of a series of fecal samples, we found that genetic predisposition to pB-ALL (Pax5 heterozygosity or ETV6-RUNX1 fusion) shaped a distinct gut microbiome. Machine learning accurately (96.8%) predicted genetic predisposition using 40 of 3983 amplicon sequence variants as proxies for bacterial species. Transplantation of either wild-type (WT) or Pax5+/- hematopoietic bone marrow cells into WT recipient mice revealed that the microbiome is shaped and determined in a donor genotype-specific manner. Gas chromatography-mass spectrometry (GC-MS) analyses of sera from WT and Pax5+/- mice demonstrated the presence of a genotype-specific distinct metabolomic profile. Taken together, our data indicate that it is a lack of commensal microbiota rather than the presence of specific bacteria that promotes leukemia in genetically predisposed mice. Future large-scale longitudinal studies are required to determine whether targeted microbiome modification in children predisposed to pB-ALL could become a successful prevention strategy.


Assuntos
Suscetibilidade a Doenças , Disbiose/complicações , Fezes/microbiologia , Microbioma Gastrointestinal , Leucemia Experimental/prevenção & controle , Fator de Transcrição PAX5/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/prevenção & controle , Animais , Feminino , Leucemia Experimental/genética , Leucemia Experimental/microbiologia , Leucemia Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/microbiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia
5.
Cancer Metastasis Rev ; 39(1): 161-171, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31902036

RESUMO

Pediatric acute lymphoblastic leukemia (ALL) is defined by recurrent chromosomal aberrations including hyperdiploidy and chromosomal translocations. Many of these aberrations originate in utero and the cells transform in early childhood through acquired secondary mutations. In this review, we will discuss the most common prenatal lesions that can lead to childhood ALL, with a special emphasis on the most common translocation in childhood ALL, t(12;21), which results in the ETV6-RUNX1 gene fusion. The ETV6-RUNX1 fusion arises prenatally and at a 500-fold higher frequency than the corresponding ALL. Even though the findings regarding the frequency of ETV6-RUNX1 were originally challenged, newer studies have confirmed the higher frequency. The prenatal origin has also been proven for other gene fusions, including KMT2A, the translocations t(1;19) and t(9;22) leading to TCF3-PBX1 and BCR-ABL1, respectively, as well as high hyperdiploidy. For most of these aberrations, there is evidence for more frequent occurrence than the corresponding leukemia incidences. We will briefly discuss what is known about the cells of origin, the mechanisms of leukemic transformation through lack of immunosurveillance, and why only a part of the carriers develops ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/embriologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Aberrações Cromossômicas , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Humanos , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética
6.
Blood Cancer Discov ; 1(3): 224-233, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33392513

RESUMO

B-cells are an integral part of the adaptive immune system and regulate innate immunity. Derived from hematopoietic stem cells they mature through a series of cell fate decisions. Complex transcriptional circuits form and dissipate dynamically during these lineage restrictions. Genomic aberrations of involved transcription factors underlie various B-cell disorders. Acquired somatic aberrations are associated with cancer, whereas germline variations predispose to both malignant and non-malignant diseases. We review the opposing role of transcription factors during B-cell development in health and disease. We focus on early B-cell leukemia and discuss novel causative gene-environment cooperations and their implications for precision medicine.


Assuntos
Linfócitos B , Leucemia , Fatores de Transcrição , Linfócitos B/fisiologia , Diferenciação Celular/genética , Interação Gene-Ambiente , Hematopoese , Células-Tronco Hematopoéticas/fisiologia , Humanos , Leucemia/genética , Leucemia/imunologia , Fatores de Transcrição/genética
7.
Blood Adv ; 3(20): 3143-3156, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31648313

RESUMO

Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post-allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post-allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post-allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.


Assuntos
Biomarcadores Tumorais , Evolução Clonal/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Seleção Genética , Criança , Pré-Escolar , Biologia Computacional/métodos , Reparo do DNA , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunofenotipagem , Lactente , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Transplante Homólogo , Proteína Supressora de Tumor p53/genética
9.
ACS Appl Mater Interfaces ; 4(8): 4062-6, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22780222

RESUMO

We report the synthesis of needle-shaped nanocrystals of Ni(5)TiO(7) utilizing a solid-phase reaction of NiO with a porous and rough TiO(2) surface produced by plasma electrolytic oxidation. The single crystalline orthorhombic nanocrystals are grown along the [010] axis, featuring a length of ∼10 µm and diameters varying from several tens of nanometers up to 200 nm. The resulted novel Ni(5)TiO(7)/TiO(2)/Ti nanoarchitectured compound composite has been proven outstandingly active as a catalyst and appears most suitable for high-temperature operation in biomass gasification. The findings may pave the way to an improved and environmentally friendly technology of energy generation.


Assuntos
Biomassa , Níquel/química , Óxidos/química , Titânio/química , Biocombustíveis , Catálise , Cristalização , Gases , Microscopia Eletrônica de Varredura/métodos , Microscopia Eletrônica de Transmissão/métodos , Modelos Químicos , Nanopartículas/química , Nanotecnologia/métodos , Oxigênio/química , Propriedades de Superfície , Temperatura
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...