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1.
Medicine (Baltimore) ; 99(24): e20733, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541525

RESUMO

INTRODUCTION: To investigate the gene rearrangement and mutation of lymphoma biomarkers including (Immunoglobulin H (IgH), Immunoglobulin kappa (IGK), Immunoglobulin lambda (IGL), and TCR) in the lymphoma diagnosis. METHODS AND ANALYSIS: Paraffin tissue samples from 240 cases diagnosed as suspected lymphoma in the department of pathology, Deyang City People's Hospital from June 2020 to June 2021 will be enrolled. Deoxyribonucleic acid extraction and Polymerase Chain Reaction (PCR) amplification will be performed in these paraffin tissue samples. Immunoglobulin and T cell receptor (TCR) rearrangement will be analyzed by hetero-double chain gel electrophoresis and BioMed-2 standardized immunoglobulin gene rearrangement detection system. In this study protocol IGH gene rearrangement, IGK gene rearrangement, both IGH and IGL gene rearrangement, both IGH and IGK gene rearrangement, both IGK and IGL gene rearrangement, both IGH, IGK and IGL gene rearrangement, TCR gene rearrangement and positive Ig/TCR rearrangement will be analyzed. DISCUSSION: In this study, we will use B and T cell lymphoma analysis focusing on IgH, IGK, IGL, and TCR gene rearrangement, so as to provide early guidance for the diagnosis of lymphoma. Second generation sequencing technology is helpful in the differential diagnosis of lymphoma. TRIAL REGISTRATION: Chinese Clinical trial registry: ChiCTR2000032366.


Assuntos
Rearranjo Gênico , Linfoma/genética , Mutação , Estudos Observacionais como Assunto/métodos , Projetos de Pesquisa , Humanos , Estudos Prospectivos
2.
Am J Pathol ; 190(3): 602-613, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32113662

RESUMO

Casitas B-lineage lymphoma (c-Cbl) is a recently identified ubiquitin ligase of nuclear ß-catenin and a suppressor of colorectal cancer (CRC) growth in cell culture and mouse tumor xenografts. We hypothesized that reduction in c-Cbl in colonic epithelium is likely to increase the levels of nuclear ß-catenin in the intestinal crypt, augmenting CRC tumorigenesis in an adenomatous polyposis coli (APCΔ14/+) mouse model. Haploinsufficient c-Cbl mice (APCΔ14/+ c-Cbl+/-) displayed a significant (threefold) increase in atypical hyperplasia and adenocarcinomas in the small and large intestines; however, no differences were noted in the adenoma frequency. In contrast to the APCΔ14/+ c-Cbl+/+ mice, APCΔ14/+ c-Cbl+/- crypts showed nuclear ß-catenin throughout the length of the crypts and up-regulation of Axin2, a canonical Wnt target gene, and SRY-box transcription factor 9, a marker of intestinal stem cells. In contrast, haploinsufficiency of c-Cbl+/- alone was insufficient to induce tumorigenesis regardless of an increase in the number of intestinal epithelial cells with nuclear ß-catenin and SRY-box transcription factor 9 in APC+/+ c-Cbl+/- mice. This study demonstrates that haploinsufficiency of c-Cbl results in Wnt hyperactivation in intestinal crypts and accelerates CRC progression to adenocarcinoma in the milieu of APCΔ14/+, a phenomenon not found with wild-type APC. While emphasizing the role of APC as a gatekeeper in CRC, this study also demonstrates that combined partial loss of c-Cbl and inactivation of APC significantly contribute to CRC tumorigenesis.


Assuntos
Adenocarcinoma/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Haploinsuficiência , Linfoma/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Adenocarcinoma/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Carcinogênese , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Linfoma/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
3.
Nature ; 579(7798): 291-296, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32103174

RESUMO

The DNA-dependent protein kinase (DNA-PK), which comprises the KU heterodimer and a catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor1. KU binds to DNA ends, initiates cNHEJ, and recruits and activates DNA-PKcs. KU also binds to RNA, but the relevance of this interaction in mammals is unclear. Here we use mouse models to show that DNA-PK has an unexpected role in the biogenesis of ribosomal RNA (rRNA) and in haematopoiesis. The expression of kinase-dead DNA-PKcs abrogates cNHEJ2. However, most mice that both expressed kinase-dead DNA-PKcs and lacked the tumour suppressor TP53 developed myeloid disease, whereas all other previously characterized mice deficient in both cNHEJ and TP53 expression succumbed to pro-B cell lymphoma3. DNA-PK autophosphorylates DNA-PKcs, which is its best characterized substrate. Blocking the phosphorylation of DNA-PKcs at the T2609 cluster, but not the S2056 cluster, led to KU-dependent defects in 18S rRNA processing, compromised global protein synthesis in haematopoietic cells and caused bone marrow failure in mice. KU drives the assembly of DNA-PKcs on a wide range of cellular RNAs, including the U3 small nucleolar RNA, which is essential for processing of 18S rRNA4. U3 activates purified DNA-PK and triggers phosphorylation of DNA-PKcs at T2609. DNA-PK, but not other cNHEJ factors, resides in nucleoli in an rRNA-dependent manner and is co-purified with the small subunit processome. Together our data show that DNA-PK has RNA-dependent, cNHEJ-independent functions during ribosome biogenesis that require the kinase activity of DNA-PKcs and its phosphorylation at the T2609 cluster.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Hematopoese/genética , Autoantígeno Ku/metabolismo , Linfoma/enzimologia , Linfoma/fisiopatologia , RNA Ribossômico 18S/metabolismo , Proteínas de Ligação ao Cálcio/genética , Domínio Catalítico/fisiologia , Reparo do DNA/genética , Ativação Enzimática/genética , Células HeLa , Humanos , Linfoma/genética , Modelos Animais , Mutação , Fosforilação , Ligação Proteica , Biossíntese de Proteínas/genética , RNA Ribossômico 18S/genética , RNA Nucleolar Pequeno/metabolismo
4.
PLoS One ; 15(2): e0229577, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32101576

RESUMO

MicroRNAs (miRNAs) inhibit protein function by silencing the translation of target mRNAs. However, in primary central nervous system lymphoma (PCNSL), the expression and functions of miRNAs are inadequately known. Here, we examined the expression of 847 miRNAs in 40 PCNSL patients with a microarray and investigated for the miRNA predictors associated with cancer immunity-related genes such as T helper cell type 1/2 (Th-1/Th-2) and regulatory T cell (T-reg) status, and stimulatory and inhibitory checkpoint genes, for prognosis prediction in PCNSL. The aim of this study is to find promising prognosis markers based on the miRNA expression in PCNSL. We detected 334 miRNAs related to 66 cancer immunity-related genes in the microarray profiling. Variable importance measured by the random survival forest analysis and Cox proportional hazards regression model elucidated that 11 miRNAs successfully constitute the survival formulae dividing the Kaplan-Meier curve of the respective PCNSL subgroups. On the other hand, univariate analysis shortlisted 23 miRNAs for overall survival times, with four miRNAs clearly dividing the survival curves-miR-101/548b/554/1202. These miRNAs regulated Th-1/Th-2 status, T-reg cell status, and immune checkpoints. The miRNAs were also associated with gene ontology terms as Ras/MAP-kinase, ubiquitin ligase, PRC2 and acetylation, CDK, and phosphorylation, and several diseases including acquired immunodeficiency syndrome, glioma, and those related to blood and hippocampus with statistical significance. In conclusion, the results demonstrated that the four miRNAs comprising miR-101/548b/554/1202 associated with cancer immunity can be a useful prognostic marker in PCNSL and would help us understand target pathways for PCNSL treatments.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Linfoma/genética , MicroRNAs/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Imunidade/genética , Estimativa de Kaplan-Meier , Linfoma/patologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Análise de Sobrevida
5.
Nat Commun ; 11(1): 685, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019925

RESUMO

IκB kinase 2 (IKK2) is well known for its pivotal role as a mediator of the canonical NF-κB pathway, which has important functions in inflammation and immunity, but also in cancer. Here we identify a novel and critical function of IKK2 and its co-factor NEMO in the activation of oncogenic c-Jun N-terminal kinase (JNK) signaling, induced by the latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). Independent of its kinase activity, the TGFß-activated kinase 1 (TAK1) mediates LMP1 signaling complex formation, NEMO ubiquitination and subsequent IKK2 activation. The tumor progression locus 2 (TPL2) kinase is induced by LMP1 via IKK2 and transmits JNK activation signals downstream of IKK2. The IKK2-TPL2-JNK axis is specific for LMP1 and differs from TNFα, Interleukin-1 and CD40 signaling. This pathway mediates essential LMP1 survival signals in EBV-transformed human B cells and post-transplant lymphoma, and thus qualifies as a target for treatment of EBV-induced cancer.


Assuntos
Linfócitos B/virologia , Herpesvirus Humano 4/fisiologia , Quinase I-kappa B/metabolismo , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Transformação Celular Viral , Herpesvirus Humano 4/genética , Humanos , Quinase I-kappa B/genética , Linfoma/enzimologia , Linfoma/genética , Linfoma/metabolismo , MAP Quinase Quinase 4/genética , MAP Quinase Quinase Quinases/genética , Camundongos , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais
6.
Int J Cancer ; 146(8): 2243-2254, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31525277

RESUMO

Constitutive activation of FGFR1, as a result of diverse chromosome translocations, is the hallmark of stem cell leukemia/lymphoma syndrome. The BCR-FGFR1 variant is unique in that the BCR component contributes a serine-threonine kinase (STK) to the N-terminal end of the chimeric FGFR1 kinase. We have deleted the STK domain and mutated the critical Y177 residue and demonstrate that the transforming activity of these mutated genes is reduced compared to the BCR-FGFR1 parental kinase. In addition, we demonstrate that deletion of the FGFR1 tyrosine kinase domain abrogates transforming ability, which is not compensated for by BCR STK activity. Unbiased screening for proteins that are inactivated as a result of loss of the BCR STK identified activated S6 kinase and SHP2 kinase. Genetic and pharmacological inhibition of SHP2 function in SCLL cells expressing BCR-FGFR1 in vitro leads to reduced viability and increased apoptosis. In vivo treatment of SCLL in mice with SHP099 leads to suppression of leukemogenesis, supporting an important role for SHP2 in FGFR1-driven leukemogenesis. In combination with the BGJ398 FGFR1 inhibitor, cell viability in vitro is further suppressed and acts synergistically with SHP099 in vivo suggesting a potential combined targeted therapy option in this subtype of SCLL disease.


Assuntos
Leucemia/metabolismo , Linfoma/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas c-bcr/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Transformação Celular Neoplásica , Sinergismo Farmacológico , Feminino , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Leucemia/tratamento farmacológico , Leucemia/genética , Leucemia/patologia , Linfoma/tratamento farmacológico , Linfoma/genética , Linfoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Fusão Oncogênica/genética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Domínios Proteicos , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-bcr/biossíntese , Proteínas Proto-Oncogênicas c-bcr/genética , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética
7.
Am J Hematol ; 95(3): 274-281, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31814157

RESUMO

Histological transformation in Waldenström macroglobulinemia (WM) is an uncommon complication, with limited data, particularly regarding the impact of MYD88 L265P mutation on transformation. We examined risk factors and outcomes associated with transformation in WM, highlighting the role of MYD88 L265P mutation. Patients with WM seen at Mayo Clinic, Rochester, USA and University Hospital of Reims, France, between 01/01/1996 and December 31, 2017 were included; 50 (4.3%) of 1147 patients transformed to a high-grade lymphoma, with median time-to-transformation of 4.5 (range 0-21) years in the transformed cohort. The MYD88 L265P mutation status was known in 435/1147 (38%) patients (406 with non-transformed WM and 29 patients in transformed cohort). On multivariate analysis, MYD88 WT status alone was an independent predictor of transformation (odds ratio, 7[95%CI: 2.1-23]; P = .003). Additionally, the MYD88 WT status was independently associated with shorter time-to-transformation (HR 7.9 [95%CI: 2.3-27; P = .001]), with a 5-year transformation rate of 16% for MYD88 WT vs 2.8% with MYD88 L265P mutated patients. Patients with transformation demonstrated a significant increase in risk of death compared to patients who did not transform (HR 5.075; 95%CI: 3.8-6.8; P < .001). In conclusion, the MYD88 WT status is an independent predictor of transformation and associated with a shorter time-to-transformation. Additionally, transformation conferred an inferior overall survival in patients with WM.


Assuntos
Transformação Celular Neoplásica/genética , Linfoma , Mutação de Sentido Incorreto , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Neoplasias/genética , Macroglobulinemia de Waldenstrom , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Linfoma/genética , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Fatores de Tempo , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/mortalidade
8.
Virchows Arch ; 476(5): 647-665, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31863183

RESUMO

Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally described "immune sanctuary" sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including MYD88 L265P and CD79B. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant-associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma [DLBCL] and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Privilégio Imunológico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma/diagnóstico , Neoplasias Testiculares/diagnóstico , Implantes de Mama/efeitos adversos , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/patologia , Educação , Feminino , Humanos , Linfoma/genética , Linfoma/imunologia , Linfoma/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/imunologia , Linfoma Anaplásico de Células Grandes/patologia , Masculino , Transdução de Sinais , Neoplasias Testiculares/genética , Neoplasias Testiculares/imunologia , Neoplasias Testiculares/patologia
9.
Hematol Oncol ; 38(1): 34-37, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31872890

RESUMO

This report summarizes a closed workshop cosponsored by the American Association for Cancer Research, the European School of Oncology, and the 15th-International Conference on Malignant Lymphoma to discuss critical open questions on liquid biopsy in lymphoid malignancies, develops a roadmap for their analytical and clinical validation, and prioritizes research areas.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/sangue , Biópsia Líquida/métodos , Linfoma/sangue , DNA Tumoral Circulante/genética , Congressos como Assunto , Humanos , Linfoma/diagnóstico , Linfoma/genética , Linfoma/terapia , Manejo de Espécimes
10.
PLoS One ; 14(12): e0226336, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31841533

RESUMO

INTRODUCTION: In southern European countries, multicentric lymphoma and leishmaniosis are the main differential diagnoses in dogs presented with generalized lymphadenomegaly. The cytological examination is in some cases inconclusive and polymerase chain reaction (PCR) for antigen receptor rearrangement (PARR) has become a common method to confirm or rule out a lymphoproliferative neoplasia. According to the literature, leishmaniosis may lead to clonal arrangements and therefore to a false diagnosis of lymphoma, but this assumption is made from a single leishmania infected dog. Therefore, the objective of this study was to prospectively evaluate results from PARR in dogs with lymphadenomegaly due to clinical leishmaniosis at the moment of diagnosis. MATERIALS AND METHODS: 31 dogs with a diagnosis of leishmaniosis based on the LeishVet guidelines were included in the study. Samples from enlarged lymph nodes were taken for cytological examination, clonality testing and Leishmania infantum PCR. RESULTS: All 31 dogs had medium to high positive antibody titers against Leishmania spp. and 30/31 had a positive Leishmania PCR from the lymph node. A polyclonal arrangement for B cells (immunoglobulin heavy chain gene) and T cells (T-cell receptor gamma chain gene) antigen receptors was found in 28/31 dogs. Two out of 31 dogs showed a monoclonal arrangement for Ig with high (1:2) and low (1:7) polyclonal background respectively; and one of the 31 dogs showed a monoclonal arrangement for T cell receptor with low (1:3) polyclonal background. CONCLUSION: Infections with Leishmania infantum resulted in clonal rearrangement, and therefore in a possible false diagnosis of lymphoma, in 3 out of 31 dogs (9.7%). Although, PARR is a useful method to differentiate lymphoma from reactive lymphoid hyperplasia in dogs with leishmaniosis, mono-/biclonal results should be interpreted carefully, especially in the presence of any degree of polyclonal background, and together with other clinicopathological findings.


Assuntos
Evolução Clonal , Doenças do Cão/imunologia , Leishmania infantum/imunologia , Leishmaniose Visceral/diagnóstico , Linfonodos/metabolismo , Linfadenopatia/diagnóstico , Animais , Evolução Clonal/genética , Evolução Clonal/imunologia , Diagnóstico Diferencial , Doenças do Cão/diagnóstico , Doenças do Cão/genética , Doenças do Cão/patologia , Cães , Feminino , Rearranjo Gênico do Linfócito B , Rearranjo Gênico do Linfócito T , Testes Genéticos/métodos , Testes Genéticos/veterinária , Leishmania infantum/genética , Leishmaniose Visceral/genética , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/patologia , Linfonodos/imunologia , Linfadenopatia/genética , Linfadenopatia/imunologia , Linfadenopatia/parasitologia , Linfoma/diagnóstico , Linfoma/genética , Linfoma/veterinária , Masculino , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/veterinária , Estudos Prospectivos , Esplenomegalia/diagnóstico , Esplenomegalia/veterinária
11.
Proc Natl Acad Sci U S A ; 116(44): 22288-22293, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31611375

RESUMO

Cancer development is driven by activated oncogenes and loss of tumor suppressors. While oncogene inhibitors have entered routine clinical practice, tumor suppressor reactivation therapy remains to be established. For the most frequently inactivated tumor suppressor p53, genetic mouse models have demonstrated regression of p53-null tumors upon p53 reactivation. While this was shown in tumor models driven by p53 loss as the initiating lesion, many human tumors initially develop in the presence of wild-type p53, acquire aberrations in the p53 pathway to bypass p53-mediated tumor suppression, and inactivate p53 itself only at later stages during metastatic progression or therapy. To explore the efficacy of p53 reactivation in this scenario, we used a reversibly switchable p53 (p53ERTAM) mouse allele to generate Eµ-Myc-driven lymphomas in the presence of active p53 and, after full lymphoma establishment, switched off p53 to model late-stage p53 inactivation. Although these lymphomas had evolved in the presence of active p53, later loss and subsequent p53 reactivation surprisingly activated p53 target genes triggering massive apoptosis, tumor regression, and long-term cure of the majority of animals. Mechanistically, the reactivation response was dependent on Cdkn2a/p19Arf, which is commonly silenced in p53 wild-type lymphomas, but became reexpressed upon late-stage p53 inactivation. Likewise, human p53 wild-type tumor cells with CRISPR-engineered switchable p53ERTAM alleles responded to p53 reactivation when CDKN2A/p14ARF function was restored or mimicked with Mdm2 inhibitors. Together, these experiments provide genetic proof of concept that tumors can respond, in an ARF-dependent manner, to p53 reactivation even if p53 inactivation has occurred late during tumor evolution.


Assuntos
Carcinogênese/genética , Terapia Genética/métodos , Linfoma/genética , Proteína Supressora de Tumor p53/genética , Células 3T3 , Animais , Apoptose , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células HCT116 , Humanos , Linfoma/terapia , Camundongos , Proteína Supressora de Tumor p53/metabolismo
12.
Blood ; 134(18): 1510-1516, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31501153

RESUMO

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.


Assuntos
Doenças Autoimunes/genética , Síndromes de Imunodeficiência/genética , Linfoma/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Doenças Autoimunes/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Síndromes de Imunodeficiência/imunologia , Linfoma/imunologia , Masculino , Linhagem , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência
13.
Clin Adv Hematol Oncol ; 17(9): 509-517, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31549972

RESUMO

In recent years, advances have been made in methods to assess response to therapy in lymphoma. Ideally, response assessment tools should be highly sensitive and specific for identifying a disease, should carry a minimal risk of harm to the patient, and should provide reproducible results. Traditional surveillance methods have included clinical assessment and, in many cases, routine surveillance imaging. Minimal residual disease (MRD) refers to the detection of disease level below that of these traditional surveillance methods. Either circulating tumor cells or their nucleic acid fragments released from necrotic/apoptotic cells can be measured in circulating peripheral blood, referred to as circulating tumor DNA (ctDNA). ctDNA can be detected with allele-specific polymerase chain reaction (ASO-PCR) or with next-generation sequencing (NGS) techniques. The use of ctDNA as a monitoring strategy in lymphoma can aid in assessment of disease burden, as well as prognostication, customization of therapy ("risk-adapted" strategies), monitoring for relapse, and consideration of early intervention ("preemptive" strategies), while reducing radiation exposure from surveillance imaging modalities that are presently used. In this review, we discuss the current state of the art in ctDNA measurement, as well as the clinical data supporting its potential utility in the management of lymphoma patients.


Assuntos
DNA Tumoral Circulante , Sequenciamento de Nucleotídeos em Larga Escala , Linfoma , Reação em Cadeia da Polimerase , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Humanos , Linfoma/sangue , Linfoma/genética , Linfoma/terapia , Neoplasia Residual
14.
EMBO J ; 38(20): e102096, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31483066

RESUMO

Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53R178E mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53-/- mice. Surprisingly, stabilization of p53R178E in Mdm2-/- mice nevertheless triggers extensive apoptosis, indicative of residual wild-type activities. Although this apoptotic activity suffices to trigger lethality of Trp53R178E ;Mdm2-/- embryos, it proves insufficient for suppression of spontaneous and oncogene-driven tumorigenesis. Trp53R178E mice develop tumors indistinguishably from Trp53-/- mice and tumors retain and even stabilize the p53R178E protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53R178E tumors exhibit remarkably better chemotherapy responses than Trp53-/- ones, resulting in enhanced eradication of p53-mutated tumor cells. Together, this provides genetic proof-of-principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Leucemia Mieloide Aguda/prevenção & controle , Linfoma/prevenção & controle , Mutação , Proteínas Proto-Oncogênicas c-mdm2/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Ciclo Celular , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Linfoma/genética , Linfoma/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Tumorais Cultivadas
15.
Methods Mol Biol ; 2031: 3-28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31473952

RESUMO

The in vitro mouse lymphoma cell assay (MLA) is one of the most widely practiced assays in genetic toxicology. MLA detects forward mutations at the thymidine kinase (Tk) locus of the L5178Y (Tk+/- -3.7.2C) cell line derived from a mouse thymic lymphoma. This assay is capable of detecting a wide range of genetic events including point mutations, deletions and multilocus, chromosomal rearrangements, mitotic recombination and nondisjunction. There are two equally accepted versions of the assay, one using soft agar cloning and the second method using liquid media cloning in 96-microwell plates. There are two morphologically distinct types of mutant colonies recovered in the MLA; small and large colony mutants. The induction of small colony mutants is associated with chemicals inducing gross chromosomal aberrations, whereas the induction of large mutant colonies is generally associated with chemicals inducing point mutations. The source and karyotype of the cell line as well as the culture conditions are important variables that could influence the assay performance. The assay when performed according to the standards recommended by the International Workshops on Genotoxicity Testing (IWGT) and the Organization of Economic Cooperation and Development Test Guideline 490 is capable of providing valuable genotoxicity hazard information as part of the overall safety assessment process of various classes of test substances.


Assuntos
Linfoma/genética , Testes de Mutagenicidade/métodos , Mutação , Timidina Quinase/genética , Animais , Linhagem Celular Tumoral , Loci Gênicos/efeitos dos fármacos , Camundongos , Mutação/efeitos dos fármacos
16.
Hum Immunol ; 80(11): 917-922, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31431297

RESUMO

Various cells from humans and animals have been established as cell lines, and their features, characteristics, and origins have been reported. Many laboratories use cell lines as model cells, which are selected to suit research purposes. We attempted to identify the ABO genotypes of 31 human leukemia and lymphoma cell lines stored in our laboratory using three methods: the PCR amplification of specific alleles (PASA), PCR-restriction fragment length polymorphism (RFLP), and the direct DNA sequencing of PCR products. We distinguished 31 human leukemia and lymphoma cell lines examined into six major ABO genotypes: A/O (A101/O01: n = 1, A101/O12: n = 4, A101/O26: n = 1, A101/O49: n = 1, A102/O01: n = 3), A/A (A101/A101: n = 1, A102/A102: n = 2), B/O (Bw29/O01: n = 1), B/B (B101/B101: n = 2), O/O (O01/O01: n = 9, O01/O02: n = 1, O01/O26: n = 1, O02/O03: n = 1), and A/B (A102/B101: n = 3). To the best of our knowledge, this is the first study to identify the ABO genotypes of various cell lines. The ABO genotypes of cell lines are important when selecting an experimental model cell for an ABO blood group study, and are essential information for cell lines. These results may be employed by research and clinical laboratories as well as in the forensic field.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Genótipo , Leucemia/genética , Linfoma/genética , Alelos , Pesquisa Biomédica , Tipagem e Reações Cruzadas Sanguíneas , Linhagem Celular Tumoral , Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Análise de Sequência de DNA
17.
Genes Dev ; 33(17-18): 1252-1264, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31395740

RESUMO

Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell-specific deletion of Max has a modest effect on B-cell development but completely abrogates Eµ-Myc-driven lymphomagenesis. While Max loss affects only a few hundred genes in normal B cells, it leads to the global down-regulation of Myc-activated genes in premalignant Eµ-Myc cells. We show that the balance between MYC-MAX and MNT-MAX interactions in B cells shifts in premalignant B cells toward a MYC-driven transcriptional program. Moreover, we found that MAX loss leads to a significant reduction in MYC protein levels and down-regulation of direct transcriptional targets, including regulators of MYC stability. This phenomenon is also observed in multiple cell lines treated with MYC-MAX dimerization inhibitors. Our work uncovers a layer of Myc autoregulation critical for lymphomagenesis yet partly dispensable for normal development.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Linfoma/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Deleção de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/farmacologia , Cinurenina/genética , Cinurenina/metabolismo , Linfoma/fisiopatologia , Camundongos , Organoides/crescimento & desenvolvimento , Organoides/fisiopatologia , Oximas/farmacologia , Sulfonamidas/farmacologia
18.
Anticancer Res ; 39(8): 4061-4064, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366488

RESUMO

BACKGROUND/AIM: Circulating tumor cells (CTCs) may have an important role in metastasis. CTC clusters, which contain fibroblasts, indicate poor prognosis. In the present study, we used our malignant lymphoma metastatic mouse model to compare the effect of a choline-deficient-diet (CDD) and the control diet (CD) on fibroblasts in CTCs. MATERIALS AND METHODS: We compared the number and morphology of CTCs in CDD and CD mice using color-coded imaging with fluorescent proteins. Malignant lymphoma EL4 cells expressing RFP were injected in the spleen of transgenic C57B/6-GFP mice, which were fed a CDD or CD. Two weeks later, we harvested and observed the number of CTCs and fibroblast-like cells both in heart blood and portal blood. Imaging of CTC morphology was performed with smeared glass slides and in culture. RESULTS AND CONCLUSION: There was no significant difference in the number of CTCs between CDD and CD mice. The number of fibroblast-like cells in the CTC microenvironment in CD mouse portal blood was significantly larger than in CDD mouse portal blood. These differences may be caused by deficiency in choline that leads to less metastasis in choline-deficient-diet-induced fatty liver.


Assuntos
Colina/metabolismo , Linfoma/sangue , Células Neoplásicas Circulantes/metabolismo , Células Estromais/metabolismo , Animais , Linhagem Celular Tumoral , Deficiência de Colina/sangue , Deficiência de Colina/genética , Deficiência de Colina/patologia , Dieta/efeitos adversos , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteínas de Fluorescência Verde/química , Humanos , Proteínas Luminescentes/química , Linfoma/genética , Linfoma/patologia , Camundongos , Camundongos Transgênicos , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , Células Estromais/patologia , Microambiente Tumoral/genética
19.
EMBO Rep ; 20(8): e47026, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31379128

RESUMO

Checkpoint kinase 1 (CHK1) is critical for S-phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumor cells have developed a strong dependence on CHK1 for survival, and hence, this kinase has developed into a promising drug target. Chk1 deficiency in mice results in blastocyst death due to G2/M checkpoint failure showing that it is an essential gene and may be difficult to target therapeutically. Here, we show that chemical inhibition of CHK1 kills murine and human hematopoietic stem and progenitor cells (HSPCs) by the induction of BCL2-regulated apoptosis. Cell death in HSPCs is independent of p53 but requires the BH3-only proteins BIM, PUMA, and NOXA. Moreover, Chk1 is essential for definitive hematopoiesis in the embryo. Noteworthy, cell death inhibition in HSPCs cannot restore blood cell formation as HSPCs lacking CHK1 accumulate DNA damage and stop dividing. Moreover, conditional deletion of Chk1 in hematopoietic cells of adult mice selects for blood cells retaining CHK1, suggesting an essential role in maintaining functional hematopoiesis. Our findings establish a previously unrecognized role for CHK1 in establishing and maintaining hematopoiesis.


Assuntos
Apoptose/genética , Células da Medula Óssea/metabolismo , Quinase 1 do Ponto de Checagem/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2/genética , Proteína 11 Semelhante a Bcl-2/metabolismo , Benzodiazepinonas/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/deficiência , Embrião de Mamíferos , Feto , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Linfoma/genética , Linfoma/metabolismo , Linfoma/patologia , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Knockout , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Quinuclidinas/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
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