RESUMO
The automotive industry is experiencing a transformation with the rapid integration of software-based systems inside vehicles, which are complex systems with multiple sensors. The use of vehicle sensor data has enabled vehicles to communicate with other entities in the connected vehicle ecosystem, such as the cloud, road infrastructure, other vehicles, pedestrians, and smart grids, using either cellular or wireless networks. This vehicle data are distributed, private, and vulnerable, which can compromise the safety and security of vehicles and their passengers. It is therefore necessary to design an access control mechanism around the vehicle data's unique attributes and distributed nature. Since connected vehicles operate in a highly dynamic environment, it is important to consider context information such as location, time, and frequency when designing a fine-grained access control mechanism. This leads to our research question: How can Attribute-Based Access Control (ABAC) fulfill connected vehicle requirements of Signal Access Control (SAC), Time-Based Access Control (TBAC), Location-Based Access Control (LBAC), and Frequency-Based Access Control (FBAC)? To address the issue, we propose a data flow model based on Attribute-Based Access Control (ABAC) called eXtensible Access Control Markup Language for Mobility (XACML4M). XACML4M adds additional components to the standard eXtensible Access Control Markup Language (XACML) to satisfy the identified requirements of SAC, TBAC, LBAC, and FBAC in connected vehicles. Specifically, these are: Vehicle Data Environment (VDE) integrated with Policy Enforcement Point (PEP), Time Extensions, GeoLocation Provider, Polling Frequency Provider, and Access Log Service. We implement a prototype based on these four requirements on a Raspberry Pi 4 and present a proof-of-concept for a real-world use case. We then perform a functional evaluation based on the authorization policies to validate the XACML4M data flow model. Finally, we conclude that our proposed XACML4M data flow model can fulfill all four of our identified requirements for connected vehicles.
RESUMO
B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 µg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.
Assuntos
Proteínas Proto-Oncogênicas c-bcl-6 , Animais , Linfócitos B/metabolismo , Humanos , Camundongos , Transcrição Gênica , Dedos de ZincoRESUMO
Flood events in West Africa have devastating impacts on the lives of people. Additionally, developments such as climate change, settlement expansion into flood-prone areas, and modification of rivers are expected to increase flood risk in the future. Policy documents have issued calls for conducting local risk assessments and understanding disaster risk in diverse aspects, leading to an increase in such research. Similarly, in a shift from flood protection to flood risk management, the consideration of various dimensions of flood risk, the necessity of addressing flood risk through an integrated strategy containing structural and non-structural measures, and the presence of residual risk are critical perspectives raised. However, the notion of "residual risk" remains yet to be taken up in flood risk management-related academic literature. This systematic review seeks to approach the notion of residual risk by reviewing information on flood impacts, common measures, and recommendations in academic literature. The review reveals various dimensions of impacts from residual flood risk aside from material damage, in particular, health impacts and economic losses. Infrastructural measures were a dominant category of measures before and after flood events and in recommendations, despite their shortcomings. Also, spatial planning interventions, a more participatory and inclusive governance approach, including local knowledge, sensitisation, and early warning systems, were deemed critical. In the absence of widespread access to insurance schemes, support from social networks after flood events emerged as the most frequent measure. This finding calls for in-depth assessments of those networks and research on potential complementary formal risk transfer mechanisms. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10113-021-01826-7.
RESUMO
The IKK-related kinases, IKKε and TBK1, have essential roles in innate immunity in part through modifying MYD88 signalling from the Toll-like receptors to regulate NF-κB signalling. We investigated the expression and function of IKKε and TBK1, in diffuse large B-cell lymphoma (DLBCL). DLBCL cell lines and patient-derived xenografts were used to determine their sensitivity to IKKε and TBK1 inhibitors. To understand the function of IKKε and TBK1 secreted factors were determined following administration of inhibitors. Gene expression microarrays were used to determine the transcriptional effects of inhibitors. Higher TBK1 mRNA levels associated with poorer clinical outcome but IKKε and TBK1 were expressed in both germinal centre and non-germinal centre types of DLBCL. Survival of cell lines Ly10, Ly03 and Pfeiffer, and of some primary human lymphoma cells, was suppressed by a small molecule IKKε/TBK1 inhibitor, DMX3433. DMX3433 reduced IL-10 production from Ly10 and repressed NF-κB mediated transcription. Inhibition of IKKε and TBK1 warrants further investigation as a potential therapeutic route to suppress NF-κB signalling in lymphoma.
Assuntos
Quinase I-kappa B/metabolismo , Interleucina-10/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Quinase I-kappa B/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fator de Transcrição RelA/metabolismoRESUMO
Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of aggressive lymphoproliferative disorders almost all of which are associated with poor clinical outcomes. Angioimmunoblastic T-cell lymphoma (AITL) and some peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) have similarities to normal CD4+ T-cell subsets in their gene expression profiles. A cell of origin model is, therefore, emerging and is likely to be refined in the future. Follicular helper (Tfh) T cells are now established as the cell of origin of AITL and about 20% of PTCL-NOS. Sequencing studies have identified recurrent genetic alterations in epigenetic modifiers, T-cell receptor signalling pathway intermediates or RHOA, most commonly a specific mutation leading to RHOA G17V. While PTCL-NOS remains a diagnosis of exclusion, advances in genomics have identified subgroups expressing transcription factors TBX 21 (Th1-like origin) and GATA3 (Th2-like origin). These findings suggest new biomarkers and new therapeutic avenues including the hypomethylating agent azacytidine, or inhibitors of proximal T-cell receptor (TCR) signalling and potentially certain monoclonal antibodies. The advances over the past few years, therefore, prompt stratified medicine approaches to test biologically based treatments and determine the clinical utility of the new disease classifications.
Assuntos
Epigênese Genética/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Linfoma de Células T Periférico , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Linfócitos T Auxiliares-Indutores/imunologia , Proteína rhoA de Ligação ao GTP , Humanos , Linfoma de Células T Periférico/classificação , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/terapia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/imunologiaRESUMO
CUDC-907, a dual PI3K/HDAC inhibitor, has been proposed to have therapeutic potential in hematopoietic malignancies. However, the molecular mechanisms of its effects in chronic lymphocytic leukaemia (CLL) remain elusive. We show that CLL cells are sensitive to CUDC-907, even under conditions similar to the protective microenvironment of proliferation centres. CUDC-907 inhibited PI3K/AKT and HDAC activity, as expected, but also suppressed RAF/MEK/ERK and STAT3 signalling and reduced the expression of anti-apoptotic BCL-2 family proteins BCL-2, BCL-xL, and MCL-1. Moreover, CUDC-907 downregulated cytokines BAFF and APRIL and their receptors BAFFR, TACI, and BCMA, thus blocking BAFF-induced NF-κB signalling. T cell chemokines CCL3/4/17/22 and phosphorylation of CXCR4 were also reduced by CUDC-907. These data indicated that CUDC-907 abrogates different protective signals and suggested that it might sensitize CLL cells to other drugs. Indeed, combinations of low concentrations of CUDC-907 with inhibitors of BCL2, BTK, or the NF-κB pathway showed a potent synergistic effect. Our data indicate that, apart from its known functions, CUDC-907 blocks multiple pro-survival pathways to overcome microenvironment protection in CLL cells. This provides a rationale to evaluate the clinical relevance of CUDC-907 in combination therapies with other targeted inhibitors.
Assuntos
Antineoplásicos/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Morfolinas/farmacologia , Pirimidinas/farmacologia , Fator Ativador de Células B/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Quimiocinas/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , NF-kappa B/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Receptores CXCR4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
Delayed lymphocyte and T-cell immune reconstitution following bendamustine-rituximab (BR) for indolent non-Hodgkin lymphoma (iNHL) has been described, but no information is available for chronic lymphocytic leukaemia (CLL). We present a population-based retrospective analysis of immune reconstitution and risk of infection following BR. Outcomes included timing/correlates of CD4+ recovery and risk of ≥grade 3 infections. Consecutively treated patients (1 April 2014 to 31 January 2017) were included (n = 295),with a median age of 65 years (range 33-92); 57% were 1st line treatments. Median cumulative bendamustine dose was 1080 mg/m2 (range 140-1440 mg/m2 ). CD4/CD8/CD19/NK subsets were available for 148 patients. Median follow-up was 24 months. Median times to lymphocyte count (ALC) recovery (≥1 × 109 /l) and CD4+ recovery (≥0·2 × 109 /l) were 26 and 24 months, respectively. Bendamustine total dose >1080 mg/m2 (hazard ratio [HR] 0·4; 95% confidence interval [CI]: 0·2-0·8), end-of-treatment ALC ≤0·4 × 109 /l (HR 0·53; 95% CI: 0·3-0·9) and CD4+ <0·1 × 109 /l 1-year post-BR (HR 0·03; 95% CI: 0·008-0·15) were covariables for delayed CD4+ recovery. ALC-recovery ≥1 × 109 /l was an unreliable predictor of CD4+ recovery (negative predictive vale 74%, positive predictive value 86%, likelihood ratio 3·3). CD4+ lymphopenia >3 years was a significant risk factor for ≥grade 3 infections (Odds ratio 3·4; 95% CI: 1·4-6·9). CD4+ recovery after BR is unexpectedly delayed and late recovery is associated with risk of serious infections. Monitoring CD4+ following BR could identify patients at high risk of delayed infections.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Transtornos Linfoproliferativos/tratamento farmacológico , Rituximab/uso terapêutico , Subpopulações de Linfócitos T/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/farmacologia , Cloridrato de Bendamustina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rituximab/farmacologiaRESUMO
Sézary syndrome is a rare aggressive leukemic variant of primary cutaneous T-cell lymphoma, typically presenting with erythroderma, lymphadenopathy, and an atypical clonal T-cell population. Though it often involves the spleen and liver, we report a case of Sézary syndrome with renal involvement that was treated successfully. Visceral involvement confers a poor prognosis requiring systemic treatment. The patient we describe was a 66-year-old man who was referred from Dermatology services for deteriorating kidney function. Polymerase chain reaction of genomic DNA from skin and kidney biopsies confirmed a clonal T-cell population matching a population isolated in peripheral blood. The patient was treated initially with alemtuzumab, which led to a significant improvement in kidney function, and he has subsequently received a successful allogeneic stem cell transplant. This case represents a rare cause of decreased kidney function and highlights the role of biopsy in patients with suspected Sézary syndrome.
Assuntos
Alemtuzumab/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Neoplasias Renais/secundário , Síndrome de Sézary/patologia , Neoplasias Cutâneas/patologia , Idoso , Biópsia por Agulha , Terapia Combinada , Seguimentos , Humanos , Imuno-Histoquímica , Testes de Função Renal , Neoplasias Renais/terapia , Masculino , Síndrome de Sézary/terapia , Neoplasias Cutâneas/terapia , Transplante Homólogo , Resultado do TratamentoRESUMO
The complex interplay between cancer cells, stromal cells, and immune cells in the tumor microenvironment (TME) regulates tumorigenesis and provides emerging targets for immunotherapies. Crosstalk between CD4(+) T cells and proliferating chronic lymphocytic leukemia (CLL) tumor B cells occurs within lymphoid tissue pseudofollicles, and investigating these interactions is essential to understand both disease pathogenesis and the effects of immunotherapy. Tumor-derived extracellular vesicle (EV) shedding is emerging as an important mode of intercellular communication in the TME. In order to characterize tumor EVs released in response to T-cell-derived TME signals, we performed microRNA (miRNA [miR]) profiling of EVs released from CLL cells stimulated with CD40 and interleukin-4 (IL-4). Our results reveal an enrichment of specific cellular miRNAs including miR-363 within EVs derived from CD40/IL-4-stimulated CLL cells compared with parental cell miRNA content and control EVs from unstimulated CLL cells. We demonstrate that autologous patient CD4(+) T cells internalize CLL-EVs containing miR-363 that targets the immunomodulatory molecule CD69. We further reveal that autologous CD4(+) T cells that are exposed to EVs from CD40/IL-4-stimulated CLL cells exhibit enhanced migration, immunological synapse signaling, and interactions with tumor cells. Knockdown of miR-363 in CLL cells prior to CD40/IL-4 stimulation prevented the ability of CLL-EVs to induce increased synapse signaling and confer altered functional properties to CD4(+) T cells. Taken together, these data reveal a novel role for CLL-EVs in modifying T-cell function that highlights unanticipated complexity of intercellular communication that may have implications for bidirectional CD4(+) T-cell:tumor interactions within the TME.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/imunologia , Comunicação Celular/imunologia , Interleucina-4/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Proteínas de Neoplasias/imunologia , Vesículas Secretórias/imunologia , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , MicroRNAs/imunologia , RNA Neoplásico/imunologia , Vesículas Secretórias/patologia , Células Tumorais CultivadasRESUMO
Antigenic stimulation via the B-cell receptor (BCR) is a major driver of the proliferation and survival of chronic lymphocytic leukemia (CLL) cells. However, the precise mechanisms by which BCR stimulation leads to accumulation of malignant cells remain incompletely understood. Here, we investigated the ability of BCR stimulation to increase messenger RNA (mRNA) translation, which can promote carcinogenesis by effects on both global mRNA translation and upregulated expression of specific oncoproteins. Re-analysis of gene expression profiles revealed striking upregulation of pathways linked to mRNA translation both in CLL cells derived from lymph nodes, the major site of antigen stimulation in vivo, and after BCR stimulation in vitro. Anti-IgM significantly increased mRNA translation in primary CLL cells, measured using bulk metabolic labeling and a novel flow cytometry assay to quantify responses at a single-cell level. These translational responses were suppressed by inhibitors of BTK (ibrutinib) and SYK (tamatinib). Anti-IgM-induced mRNA translation was associated with increased expression of translation initiation factors eIF4A and eIF4GI, and reduced expression of the eIF4A inhibitor, PDCD4. Anti-IgM also increased mRNA translation in normal blood B cells, but without clear modulatory effects on these factors. In addition, anti-IgM increased translation of mRNA-encoding MYC, a major driver of disease progression. mRNA translation is likely to be an important mediator of the growth-promoting effects of antigen stimulation acting, at least in part, via translational induction of MYC. Differences in mechanisms of translational regulation in CLL and normal B cells may provide opportunities for selective therapeutic attack.
Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/genética , Receptores de Antígenos de Linfócitos B/imunologia , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Anticorpos Anti-Idiotípicos/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Linhagem Celular Tumoral , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Piperidinas , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/genética , Quinase Syk , Células Tumorais CultivadasRESUMO
BACKGROUND: We report a fatal case of disseminated adenovirus infection in a non-transplant haematology adult patient with chronic lymphocytic leukaemia who had completed combination chemoimmunotherapy a few months before developing respiratory symptoms. In such non-transplant patients, monitoring for adenovirus in the blood is not routine. However, with adenoviruses, when there is a more peripheral (i.e. non-blood) site of infection such as the chest, serial adenovirus monitoring in blood for the duration of that illness may be warranted. CASE PRESENTATION: This case started with an initial bacterial chest infection that responded to treatment, followed by an adenovirus pneumonitis that disseminated to his blood a week later with levels of up to 92 million adenovirus DNA copies/ml. Despite prompt treatment with cidofovir, his respiratory function continued to deteriorate over the next two weeks and he was moved to intensive care. Intravenous immunoglobulin and ribavirin were subsequently added to his treatment. However, he died soon after this with a final adenovirus load of 20 million copies/ml in his blood. CONCLUSIONS: We recommend that even in non-transplant haematology patients, where such patients present with an acute respiratory adenovirus infection, teams should consider checking the blood for adenovirus to check for signs of disseminated infection. The earlier this can be tested, the earlier treatment can be initiated (if adenovirus positive), which may produce more successful clinical outcomes.
Assuntos
Infecções por Adenovirus Humanos/diagnóstico , Leucemia Linfocítica Crônica de Células B/diagnóstico , Adenoviridae/genética , Adenoviridae/isolamento & purificação , Infecções por Adenovirus Humanos/complicações , Infecções por Adenovirus Humanos/virologia , Antineoplásicos/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/microbiologia , Cidofovir , Citosina/análogos & derivados , Citosina/uso terapêutico , DNA Viral/genética , DNA Viral/metabolismo , Quimioterapia Combinada , Evolução Fatal , Haemophilus influenzae/isolamento & purificação , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Reação em Cadeia da Polimerase , Tomografia Computadorizada por Raios X , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
We demonstrate the usefulness of synthetic lethal screening of a conditionally BCL6-deficient Burkitt lymphoma cell line, DG75-AB7, with a library of small molecules to determine survival pathways suppressed by BCL6 and suggest mechanism-based treatments for lymphoma. Lestaurtinib, a JAK2 inhibitor and one of the hits from the screen, repressed survival of BCL6-deficient cells in vitro and reduced growth and proliferation of xenografts in vivo BCL6 deficiency in DG75-AB7 induced JAK2 mRNA and protein expression and STAT3 phosphorylation. Surface IL10RA was elevated by BCL6 deficiency, and blockade of IL10RA repressed STAT3 phosphorylation. Therefore, we define an IL10RA/JAK2/STAT3 pathway each component of which is repressed by BCL6. We also show for the first time that JAK2 is a direct BCL6 target gene; BCL6 bound to the JAK2 promoter in vitro and was enriched by ChIP-seq. The place of JAK2 inhibitors in the treatment of diffuse large B-cell lymphoma has not been defined; we suggest that JAK2 inhibitors might be most effective in poor prognosis ABC-DLBCL, which shows higher levels of IL10RA, JAK2, and STAT3 but lower levels of BCL6 than GC-DLBCL and might be usefully combined with novel approaches such as inhibition of IL10RA.
Assuntos
Linfoma de Burkitt/tratamento farmacológico , Carbazóis/farmacologia , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Janus Quinase 2/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-6/biossíntese , Fator de Transcrição STAT3/metabolismo , Animais , Linfoma de Burkitt/genética , Linfoma de Burkitt/metabolismo , Linhagem Celular Tumoral , Furanos , Humanos , Subunidade alfa de Receptor de Interleucina-10/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Camundongos , Camundongos SCID , Proteínas Proto-Oncogênicas c-bcl-6/genética , Fator de Transcrição STAT3/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Follicular helper T-cells (Tfh cells) are a subset of CD4(+) T-cells that are essential for normal production of high affinity antibodies. Tfh cells characteristically produce IL21 and IL4 and show high expression of surface markers CXCR5, ICOS, PDCD1 (PD-1) and the chemokine CXCL13. In this review we will focus on the emerging links between Tfh cells and subtypes of T-cell non-Hodgkin lymphoma: angioimmunoblastic T-cell lymphoma (AITL) and ~20% of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) have surface marker features of Tfh cells and share a spectrum of genetic abnormalities. The recurrent genetic abnormalities associated with AITL include mutations in epigenetic modifiers such as TET2 and DNMT3A and the motility and adhesion gene, RHOA, is mutated in up to 70% of cases. ~20% of PTCL-NOS demonstrate RHOA mutations and have other characteristics suggesting an origin in Tfh cells. The recognition that specific genetic and surface markers are associated with malignant Tfh cells suggests that the next few years will bring major changes in diagnostic and treatment possibilities. For example, antibodies against IL21, PDCD1 and ICOS are already in clinical trials for autoimmune disease or other malignancies and antibodies against CXCL13 are in pre-clinical development.
Assuntos
Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/imunologia , Linfoma de Células T/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacosRESUMO
Developmental stage-specific regulation of BCL2 occurs during B-cell maturation and has a role in normal immunity. CD40 signaling promotes proliferation and rescues B-cells from apoptosis, partly through induction of BCL2L1 and BCL2A1 and repression of BCL2. We previously showed that a stromal cell/CD40 ligand (CD154) culture system reproduced this switch in survival protein expression in primary human leukemic B-cells and we employed this model system to investigate BCL2 repression. BCL2 was post-transcriptionally regulated and the repressed BCL2 mRNA was associated with non-polysomal, but dense fractions on sucrose density gradients. Microarrays identified a set of miRNA that were induced by culture conditions and potentially able to bind to the BCL2 3'-UTR. Luciferase reporter assays demonstrated that miR-125b and miR-155 repressed BCL2 mRNA but while stromal cell contact alone was sufficient to induce strongly miR-125b this did not cause BCL2 repression. miR-155, which is the most abundant miRNA under basal conditions, specifically required CD154 for further induction above a threshold to exert its full repressive effects. Anti-miR-125b and anti-miR-155 prevented CD154-mediated repression of BCL2 and reduced CD154-mediated proliferation in the MEC1 B-cell line. We suggest that miR-155 and miR-125b, which are induced by CD154 and stromal cell signals, contribute to regulating proliferation and that BCL2 is one of their target mRNAs.
Assuntos
Ligante de CD40/metabolismo , Proliferação de Células , Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , RNA Neoplásico/metabolismo , Regiões 3' não Traduzidas/genética , Ligante de CD40/genética , Linhagem Celular Tumoral , Humanos , Leucemia Linfocítica Crônica de Células B/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Neoplásico/genéticaRESUMO
The PATZ1 gene encoding a POZ/AT-hook/Kruppel zinc finger (PATZ) transcription factor, is considered a cancer-related gene because of its loss or misexpression in human neoplasias. As for other POZ/domain and Kruppel zinc finger (POK) family members, the transcriptional activity of PATZ is due to the POZ-mediated oligomer formation, suggesting that it might be not a typical transactivator but an architectural transcription factor, thus functioning either as activator or as repressor depending on the presence of proteins able to interact with it. Therefore, to better elucidate PATZ function, we searched for its molecular partners. By yeast two-hybrid screenings, we found a specific interaction between PATZ and BCL6, a human oncogene that plays a key role in germinal center (GC) derived neoplasias. We demonstrate that PATZ and BCL6 interact in germinal center-derived B lymphoma cells, through the POZ domain of PATZ. Moreover, we show that PATZ is able to bind the BCL6 regulatory region, where BCL6 itself acts as a negative regulator, and to contribute to negatively modulate its activity. Consistently, disruption of one or both Patz1 alleles in mice causes focal expansion of thymus B cells, in which BCL6 is up-regulated. This phenotype was almost completely rescued by crossing Patz1(+/-) with Bcl6(+/-) mice, indicating a key role for Bcl6 expression in its development. Finally, a significant number of Patz1 knock-out mice (both heterozygous and homozygous) also develop BCL6-expressing lymphomas. Therefore, the disruption of one or both Patz1 alleles may favor lymphomagenesis by activating the BCL6 pathway.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas Repressoras/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Imunoprecipitação da Cromatina , Primers do DNA , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Camundongos , Camundongos Knockout , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-6 , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
There is now a plethora of new precision medicines for B-cell malignancy including 'classical' kinase inhibitors, rationally designed inhibitors of anti-apoptotic proteins and antibody or antibody drug/toxin conjugates with functional properties. Some are showing spectacular single agent activity in early phase clinical studies and may reduce or, in combination, even obviate the need for chemotherapy. Nevertheless, significant problems remain if these medicines are to be introduced into routine clinical practice in a rational and affordable manner. Firstly, precision medicines must be carefully matched in a mechanistic fashion with specific subtypes of disease. Whilst sensitivity may be predicted by the detection of key mutations or by expression of target molecules, for therapies that depend on intact intracellular signalling pathways, functional assessment on viable primary malignant cells will be necessary using assays that faithfully mimic in vivo conditions. A second, but no less important challenge is to define mechanism-based synergistic combinations associated with minimal toxicities rather than simply adding new precision medicines to existing chemotherapeutic regimens. Finally, a closer, open, two-way interaction between academic medicine and the pharmaceutical industry will be necessary to achieve these aims. Implementing such changes would change radically how and where patients with B-cell malignancies are managed.
Assuntos
Antineoplásicos/farmacologia , Leucemia de Células B/tratamento farmacológico , Linfoma/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Animais , Antineoplásicos/uso terapêutico , Humanos , Leucemia de Células B/metabolismo , Linfoma/metabolismoRESUMO
Chronic lymphocytic leukaemia (CLL) cells encounter T-cells and proliferate in response to T-cell signals in the lymph node microenvironment. In this report we determined interleukin 21 (IL21) function in CLL and showed that IL21 and interleukin 4 (IL4) act co-operatively to promote leukaemic cell proliferation without apoptosis or differentiation We further show that IL21 increased side population (SP) cells, which are associated with resistance to chemotherapy and increased self-renewal capacity in CLL. IL21 and IL4 are the major cytokines produced by the recently described CD4(+) T follicular helper (Tfh) cell subset. Determination of Tfh cells in peripheral blood showed that patients had significantly increased numbers as compared to normal subjects although no association was found between Tfh numbers and IGHV gene mutational status or clinical stage. Our data suggests that the Tfh cytokines, IL4 and IL21, contribute to driving leukaemic cell proliferation in the lymph node microenvironment, and may contribute to the specific production of cells resistant to conventional chemotherapy. We suggest that increased circulating Tfh cells is a component of T-cell dysregulation in CLL. Our findings have implications for the therapeutic use of IL21.