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1.
Bioessays ; 46(9): e2400033, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39058907

RESUMO

B-cell Acute Lymphoblastic Leukemia (B-ALL) is the most common pediatric cancer, arising most often in children aged 2-5 years. This distinctive age distribution hints at an association between B-ALL development and disrupted immune system function during a susceptible period during childhood, possibly triggered by early exposure to infection. While cure rates for childhood B-ALL surpass 90% in high-income nations, survivors suffer from diminished quality of life due to the side effects of treatment. Consequently, understanding the origins and evolution of B-ALL, and how to prevent this prevalent childhood cancer, is paramount to alleviate this substantial health burden. This article provides an overview of our current understanding of the etiology of childhood B-ALL and explores how this knowledge can inform preventive strategies.


Assuntos
Progressão da Doença , Humanos , Criança , Pré-Escolar , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia de Células B/patologia
2.
Trends Immunol ; 42(5): 371-374, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33773925

RESUMO

The prevalence of childhood B cell acute lymphoblastic leukemia (B-ALL) is increasing, particularly in developed countries. There is no clear explanation for this increment, but recent data suggest that, besides genetic predisposition, stress in the immune system (e.g., an infection) might have an important role in B-ALL leukemogenesis. Here, we speculate on how this knowledge might impact B-ALL prevention strategies.


Assuntos
Leucemia de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Predisposição Genética para Doença , Humanos
3.
Nature ; 558(7711): E5, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29849140

RESUMO

In Fig. 3c of this Letter, the the effects of CRISPR-Cas9-mediated deletion of NR3C1, TXNIP and CNR2 in patient-derived B-lineage leukaemia cells were shown. For curves depicting NR3C1 (left graph), data s for TXNIP (middle graph) were inadvertently plotted. This figure has been corrected online, and the original Fig. 3c is shown as Supplementary Information to this Amendment for transparency. The error does not affect the conclusions of the Letter. In addition, Source Data files have been added for the Figs. 1-4 and Extended Data Figs. 1-10 of the original Letter.

4.
Blood ; 137(13): 1741-1753, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33024996

RESUMO

Diffuse large B-cell lymphomas (DLBCLs) are clinically and genetically heterogeneous tumors. Deregulation of diverse biological processes specific to B cells, such as B-cell receptor (BCR) signaling and motility regulation, contribute to lymphomagenesis. Human germinal center associated lymphoma (HGAL) is a B-cell-specific adaptor protein controlling BCR signaling and B lymphocyte motility. In normal B cells, it is expressed in germinal center (GC) B lymphocytes and promptly downregulated upon further differentiation. The majority of DLBCL tumors, primarily GC B-cell types, but also activated types, express HGAL. To investigate the consequences of constitutive expression of HGAL in vivo, we generated mice that conditionally express human HGAL at different stages of hematopoietic development using 3 restricted Cre-mediated approaches to initiate expression of HGAL in hematopoietic stem cells, pro-B cells, or GC B cells. Following immune stimulation, we observed larger GCs in mice in which HGAL expression was initiated in GC B cells. All 3 mouse strains developed DLBCL at a frequency of 12% to 30% starting at age 13 months, leading to shorter survival. Immunohistochemical studies showed that all analyzed tumors were of the GC B-cell type. Exon sequencing revealed mutations reported in human DLBCL. Our data demonstrate that constitutive enforced expression of HGAL leads to DLBCL development.


Assuntos
Carcinogênese/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas dos Microfilamentos/genética , Animais , Carcinogênese/patologia , Linhagem Celular , Feminino , Mutação com Ganho de Função , Regulação Neoplásica da Expressão Gênica , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Endogâmicos C57BL
5.
Nature ; 542(7642): 479-483, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28192788

RESUMO

B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.


Assuntos
Linfócitos B/metabolismo , Metabolismo Energético/genética , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Fatores de Transcrição/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Linfócitos B/efeitos dos fármacos , Carcinogênese/genética , Proteínas de Transporte/agonistas , Proteínas de Transporte/metabolismo , Morte Celular , Imunoprecipitação da Cromatina , Ciclo do Ácido Cítrico , Modelos Animais de Doenças , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Fator de Transcrição Ikaros/metabolismo , Camundongos , Camundongos Transgênicos , Fator de Transcrição PAX5/deficiência , Fator de Transcrição PAX5/genética , Fator de Transcrição PAX5/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Ácido Pirúvico/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Receptores de Glucocorticoides/metabolismo , Análise de Sequência de RNA
6.
Int J Mol Sci ; 24(14)2023 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-37511301

RESUMO

Cancer stem cells (CSCs) are now well-established as key players in tumor initiation, progression, and therapy resistance [...].


Assuntos
Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia
7.
EMBO J ; 37(14)2018 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-29880602

RESUMO

The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of Lmo2 at different stages of B-cell development induces systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T-ALL to current therapies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinogênese , Transformação Celular Neoplásica , Proteínas com Domínio LIM/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/fisiologia , Histocitoquímica , Camundongos , Timo/patologia
8.
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
9.
Int J Mol Sci ; 23(14)2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35886910

RESUMO

Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a "multi-step" or "multi-hit" mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these "first-hits" occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic "hits" will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the "multi-step" process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease.


Assuntos
Síndromes Mielodisplásicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Pré-Leucemia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pré-Leucemia/genética , Translocação Genética
11.
Int J Mol Sci ; 21(6)2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32213936

RESUMO

To produce the wide range of blood and immune cell types, haematopoietic stem cells can "choose" directly from the entire spectrum of blood cell fate-options. Affiliation to a single cell lineage can occur at the level of the haematopoietic stem cell and these cells are therefore a mixture of some pluripotent cells and many cells with lineage signatures. Even so, haematopoietic stem cells and their progeny that have chosen a particular fate can still "change their mind" and adopt a different developmental pathway. Many of the leukaemias arise in haematopoietic stem cells with the bulk of the often partially differentiated leukaemia cells belonging to just one cell type. We argue that the reason for this is that an oncogenic insult to the genome "hard wires" leukaemia stem cells, either through development or at some stage, to one cell lineage. Unlike normal haematopoietic stem cells, oncogene-transformed leukaemia stem cells and their progeny are unable to adopt an alternative pathway.


Assuntos
Linhagem da Célula , Hematopoese , Leucemia/sangue , Animais , Regulação Neoplásica da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia/genética , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo
12.
Blood ; 129(19): 2645-2656, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28288979

RESUMO

CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 overexpression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B cells, we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes. However, B cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions, enriched for Myc DNA binding motifs, and showed Myc binding. Through the analysis of CREBBP mutations from a large cohort of primary human FL and DLBCL, we show a significant difference in the spectrum of CREBBP mutations in these 2 diseases, with higher frequencies of nonsense/frameshift mutations in DLBCL compared with FL. Together, our data therefore provide important links between Crebbp inactivation and Bcl2 dependence and show a role for Crebbp inactivation in the induction of Myc expression. We suggest this may parallel the role of CREBBP frameshift/nonsense mutations in DLBCL that result in loss of the protein, but may contrast the role of missense mutations in the lysine acetyltransferase domain that are more frequently observed in FL and yield an inactive protein.


Assuntos
Linfócitos B/patologia , Proteína de Ligação a CREB/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Epigênese Genética , Deleção de Genes , Humanos , Linfoma Folicular/genética , Camundongos , Camundongos Transgênicos , Mutação
13.
Bioelectromagnetics ; 40(5): 343-353, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31157932

RESUMO

Exposure to extremely low-frequency magnetic fields (ELF-MFs) has been classified by the International Agency for Research on Cancer (IARC) as "possibly carcinogenic to humans," based on limited scientific evidence concerning childhood leukemia. This assessment emphasized the lack of appropriate animal models recapitulating the natural history of this disease. Childhood B-cell acute lymphoblastic leukemia (B-ALL) is the result of complex interactions between genetic susceptibility and exposure to exogenous agents. The most common chromosomal alteration is the ETV6-RUNX1 fusion gene, which confers a low risk of developing the malignancy by originating a preleukemic clone requiring secondary hits for full-blown disease to appear. To develop potential prophylactic interventions, we need to identify the environmental triggers of the second hit. Recently, we generated a B-ALL mouse model of the human ETV6-RUNX1+ preleukemic state. Here, we present the results from the ARIMMORA pilot study, obtained by exposing 34 Sca1-ETV6-RUNX1 mice (vs. 27 unexposed) to a 50 Hz magnetic field of 1.5 mT with both fundamental and harmonic content, with an on/off cycle of 10 min/5 min, for 20 h/day, from conception until 3 months of age. Mice were monitored until 2 years of age and peripheral blood was periodically analyzed by flow cytometry. One of the exposed mice developed B-ALL while none of the non-exposed did. Although the results are statistically non-significant due to the limited number of mice used in this pilot experiment, overall, the results show that the newly developed Sca1-ETV6-RUNX1 mouse can be successfully used for ELF-MF exposure studies about the etiology of childhood B-ALL. Bioelectromagnetics. 2019;40:343-353. © 2019 Bioelectromagnetics Society.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Campos Eletromagnéticos/efeitos adversos , Leucemia Experimental , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Proto-Oncogênicas c-ets/genética , Ondas de Rádio/efeitos adversos , Proteínas Repressoras/genética , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Feminino , Humanos , Leucemia Experimental/genética , Leucemia Experimental/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Repressoras/metabolismo , Variante 6 da Proteína do Fator de Translocação ETS
14.
Int J Mol Sci ; 21(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861691

RESUMO

Cancer-stem-cell theory states that most, if not all, cancers arise from a stem/uncommitted cell. This theory revolutionised our view to reflect that cancer consists of a hierarchy of cells that mimic normal cell development. Elegant studies of twins who both developed acute lymphoblastic leukaemia in childhood revealed that at least two genomic insults are required for cancer to develop. These 'hits' do not appear to confer a growth advantage to cancer cells, nor do cancer cells appear to be better equipped to survive than normal cells. Cancer cells created by investigators by introducing specific genomic insults generally belong to one cell lineage. For example, transgenic mice in which the LIM-only 2 (LMO2,associated with human acute T-lymphoblastic leukaemia) and BCR-ABLp210 (associated with human chronic myeloid leukaemia) oncogenes were active solely within the haematopoietic stem-cell compartment developed T-lymphocyte and neutrophil lineage-restricted leukaemia, respectively. This recapitulated the human form of these diseases. This 'hardwiring' of lineage affiliation, either throughout leukaemic stem cell development or at a particular stage, is different to the behaviour of normal haematopoietic stem cells. While normal cells directly commit to a developmental pathway, they also remain versatile and can develop into a terminally differentiated cell that is not part of the initial lineage. Many cancer stem cells do not have this versatility, and this is an essential difference between normal and cancer stem cells. In this report, we review findings that support this notion.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Leucemia/genética , Células-Tronco Neoplásicas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem da Célula , Proteínas de Fusão bcr-abl/genética , Humanos , Proteínas com Domínio LIM/genética , Leucemia/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas/genética
15.
Proc Natl Acad Sci U S A ; 112(10): E1116-25, 2015 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-25713363

RESUMO

Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfoma Folicular/genética , Mutação , Células-Tronco Neoplásicas/patologia , Proteína de Ligação a CREB/genética , Cromatina/metabolismo , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Linfoma Folicular/imunologia , Reação em Cadeia da Polimerase
16.
Int J Mol Sci ; 19(5)2018 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29772764

RESUMO

Due to the clonal nature of human leukemia evolution, all leukemic cells carry the same leukemia-initiating genetic lesions, independently of the intrinsic tumoral cellular heterogeneity. However, the latest findings have shown that the mode of action of oncogenes is not homogeneous throughout the developmental history of leukemia. Studies on different types of hematopoietic tumors have shown that the contribution of oncogenes to leukemia is mainly mediated through the epigenetic reprogramming of the leukemia-initiating target cell. This driving of cancer by a malignant epigenetic stem cell rewiring is, however, not exclusive of the hematopoietic system, but rather represents a common tumoral mechanism that is also at work in epithelial tumors. Tumoral epigenetic reprogramming is therefore a new type of interaction between genes and their target cells, in which the action of the oncogene modifies the epigenome to prime leukemia development by establishing a new pathological tumoral cellular identity. This reprogramming may remain latent until it is triggered by either endogenous or environmental stimuli. This new view on the making of leukemia not only reveals a novel function for oncogenes, but also provides evidence for a previously unconsidered model of leukemogenesis, in which the programming of the leukemia cellular identity has already occurred at the level of stem cells, therefore showing a role for oncogenes in the timing of leukemia initiation.


Assuntos
Leucemia/etiologia , Leucemia/metabolismo , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Reprogramação Celular , Meio Ambiente , Epigênese Genética , Predisposição Genética para Doença , Hematopoese/genética , Humanos , Leucemia/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Oncogenes
17.
EMBO J ; 32(11): 1502-13, 2013 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-23632857

RESUMO

Tumour-associated oncogenes induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumour cells. However, recent evidences have revealed that oncogenes are only essential for the proliferation of some specific tumour cell types, but not all. Indeed, the latest studies of the interactions between the oncogene and its target cell have shown that oncogenes contribute to cancer development not only by inducing proliferation but also by developmental reprogramming of the epigenome. This provides the first evidence that tumorigenesis can be initiated by stem cell reprogramming, and uncovers a new role for oncogenes in the origin of cancer. Here we analyse these evidences and propose an updated model of oncogene function that can explain the full range of genotype-phenotype associations found in human cancer. Finally, we discuss how this vision opens new avenues for developing novel anti-cancer interventions.


Assuntos
Transformação Celular Neoplásica/genética , Estudos de Associação Genética , Neoplasias/genética , Oncogenes/fisiologia , Animais , Biologia Celular , Proliferação de Células , Transformação Celular Neoplásica/patologia , Instabilidade Cromossômica , Humanos , Camundongos , Modelos Biológicos , Mutação , Neoplasias/patologia , Neoplasias/terapia , Células-Tronco Neoplásicas , Oncogenes/genética
18.
Proc Natl Acad Sci U S A ; 111(1): 255-60, 2014 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-24367082

RESUMO

Ubiquitous expression of a resident K-Ras(G12V) oncogene in adult mice revealed that most tissues are resistant to K-Ras oncogenic signals. Indeed, K-Ras(G12V) expression only induced overt tumors in lungs. To identify these transformation-permissive cells, we induced K-Ras(G12V) expression in a very limited number of adult lung cells (0.2%) and monitored their fate by X-Gal staining, a surrogate marker coexpressed with the K-Ras(G12V) oncoprotein. Four weeks later, 30% of these cells had proliferated to form small clusters. However, only SPC(+) alveolar type II (ATII) cells were able to form hyperplastic lesions, some of which progressed to adenomas and adenocarcinomas. In contrast, induction of K-Ras(G12V) expression in lung cells by intratracheal infection with adenoviral-Cre particles generated hyperplasias in all regions except the proximal airways. Bronchiolar and bronchioalveolar duct junction hyperplasias were primarily made of CC10(+) Clara cells. Some of them progressed to form benign adenomas. However, only alveolar hyperplasias, exclusively made up of SPC(+) ATII cells, progressed to yield malignant adenocarcinomas. Adenoviral infection induced inflammatory infiltrates primarily made of T and B cells. This inflammatory response was essential for the development of K-Ras(G12V)-driven bronchiolar hyperplasias and adenomas, but not for the generation of SPC(+) ATII lesions. Finally, activation of K-Ras(G12V) during embryonic development under the control of a Sca1 promoter yielded CC10(+), but not SPC(+), hyperplasias, and adenomas. These results, taken together, illustrate that different types of lung cells can generate benign lesions in response to K-Ras oncogenic signals. However, in adult mice, only SPC(+) ATII cells were able to yield malignant adenocarcinomas.


Assuntos
Adenocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes ras , Neoplasias Pulmonares/metabolismo , Pulmão/citologia , Proteínas ras/metabolismo , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adenoviridae/metabolismo , Alelos , Animais , Bronquíolos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Separação Celular , Transformação Celular Neoplásica , Citometria de Fluxo , Perfilação da Expressão Gênica , Inflamação , Neoplasias Pulmonares/genética , Camundongos , Camundongos Transgênicos , Oncogenes , Regiões Promotoras Genéticas , Alvéolos Pulmonares/metabolismo , Transdução de Sinais , Células-Tronco/citologia
19.
Semin Cancer Biol ; 32: 3-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24530939

RESUMO

Cancer is a clonal malignant disease originated in a single cell and characterized by the accumulation of partially differentiated cells that are phenotypically reminiscent of normal stages of differentiation. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumor cells. However, recent evidences have revealed that cancer stem cells could arise through a tumor stem cell reprogramming mechanism, suggesting that genetic lesions that initiate the cancer process might be dispensable for tumor progression and maintenance. This review addresses the impact of these results toward a better understanding of cancer development and proposes new approaches to treat cancer in the future.


Assuntos
Transformação Celular Neoplásica/genética , Reprogramação Celular/genética , Neoplasias/genética , Células-Tronco Neoplásicas , Oncogenes/genética , Animais , Diferenciação Celular/genética , Modelos Animais de Doenças , Humanos , Camundongos , Modelos Biológicos , Neoplasias/terapia
20.
Semin Cancer Biol ; 35 Suppl: S25-S54, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25892662

RESUMO

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.


Assuntos
Proteínas de Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias/patologia , Neoplasias/terapia , Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/biossíntese , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/efeitos dos fármacos
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