Ribosomal proteins are pivotal to development and tissue homeostasis. RP Large P1 (Rplp1) overexpression is associated with tumorigenesis. However, the physiological function of Rplp1 in mammalian ...development remains unknown. In this study, we disrupted Rplp1 in the mouse germline and central nervous system (Rplp1CNSΔ). Rplp1 heterozygosity caused body size reductions, male infertility, systemic abnormalities in various tissues and a high frequency of early postnatal death. Rplp1CNSΔ newborn mice exhibited perinatal lethality and brain atrophy with size reductions of the neocortex, midbrain and ganglionic eminence. The Rplp1 knockout neocortex exhibited progenitor cell proliferation arrest and apoptosis due to the dysregulation of key cell cycle and apoptosis regulators (cyclin A, cyclin E, p21CIP1, p27KIP1, p53). Similarly, Rplp1 deletion in pMEFs led to proliferation arrest and premature senescence. Importantly, Rplp1 deletion in primary mouse embryonic fibroblasts did not alter global protein synthesis, but did change the expression patterns of specific protein subsets involved in protein folding and the unfolded protein response, cell death, protein transport and signal transduction, among others. Altogether, we demonstrated that the translation "fine-tuning" exerted by Rplp1 is essential for embryonic and brain development and for proper cell proliferation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Surface expression of a functional B cell antigen receptor (BCR) is essential for the survival and proliferation of mature B cells. Most types of B‐cell lymphoproliferative disorders retain ...surface BCR expression, including B‐cell non‐Hodgkin lymphomas (B‐NHL) and chronic lymphocytic leukemia (CLL). Targeting BCR effectors in B‐NHL cell lines in vitro has indicated that this signaling axis is crucial for malignant B cell growth. This has led to the development of inhibitors of BCR signaling, which are currently used for the treatment of CLL and several B‐NHL subtypes. Recent studies based on conditional BCR inactivation in a MYC‐driven mouse B‐cell lymphoma model have revisited the role of the BCR in MYC‐expressing tumor B cells. Indeed, lymphoma cells losing BCR expression continue to grow unless subjected to competition with their BCR‐expressing counterparts, which causes their elimination. Here, we discuss the molecular nature of the fitness signal delivered by the BCR to MYC‐expressing malignant B cells, ensuring their preferential persistence within a rapidly expanding tumor population. We also review growing evidence of Ig‐negative cases belonging to several B‐NHL subtypes and CLL, and discuss the clinical implications of these findings in relation to an emerging picture of clinical resistances to anti‐BCR therapies.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The Sin3 transcriptional regulator homolog A (Sin3A) is the core member of a multiprotein chromatin‐modifying complex. Its inactivation at the CD4/CD8 double‐negative stage halts further thymocyte ...development. Among various functions, Sin3A regulates STAT3 transcriptional activity, central to the differentiation of Th17 cells active in inflammatory disorders and opportunistic infections. To further investigate the consequences of conditional Sin3A inactivation in more mature precursors and post‐thymic T cell, we have generated CD4‐Cre and CD4‐CreERT2 Sin3AF/F mice. Sin3A inactivation in vivo hinders both thymocyte development and peripheral T‐cell survival. In vitro, in Th17 skewing conditions, Sin3A‐deficient cells proliferate and acquire memory markers and yet fail to properly upregulate Il17a, Il23r, and Il22. Instead, IL‐2+ and FOXP3+ are mostly enriched for, and their inhibition partially rescues IL‐17A+ T cells. Notably, Sin3A deletion also causes an enrichment of genes implicated in the mTORC1 signaling pathway, overt STAT3 activation, and aberrant cytoplasmic RORγt accumulation. Thus, together our data unveil a previously unappreciated role for Sin3A in shaping critical signaling events central to the acquisition of immunoregulatory T‐cell phenotypes.
Synopsis
This study identifies a role for the transcriptional regulator Sin3A in shaping Th‐17 differentiation. Inducible Sin3A deletion causes overt STAT3 activation and aberrant cytoplasmic RORγt localization hindering IL‐17A levels in favor of Foxp3 expression.
The transcriptional regulator Sin3A contributes to CD4 T‐cell development and differentiation.
Sin3A inactivation in mature T cells promotes mTORC1 signaling, STAT3 activation, and aberrant cytoplasmic RORγt accumulation.
Sin3A balances IL‐17A, IL‐2, and Foxp3, thereby shaping the immunoregulatory potential of Th17 lymphocytes.
This study identifies a role for the transcriptional regulator Sin3A in shaping Th‐17 differentiation. Inducible Sin3A deletion causes overt STAT3 activation and aberrant cytoplasmic RORγt localization hindering IL‐17A levels in favor of Foxp3 expression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of ...activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR
) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR
) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR
tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3β) activity to support MYC-controlled gene expression. BCR
tumour cells exhibit increased GSK3β activity and are rescued from their competitive growth disadvantage by GSK3β inhibition. BCR
lymphoma variants that restore competitive fitness normalize GSK3β activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR
tumour cells.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
5.
Myc and the Warburg Effect Casola, Stefano; Varano, Gabriele; Perucho, Laura ...
Blood,
11/2018, Volume:
132, Issue:
Supplement 1
Journal Article
Peer reviewed
Open access
Mature B cells recognize and respond in a highly-specific fashion to a multitude of environmental antigens through membrane-bound immunoglobulins forming together with the Igα and Igβ proteins a ...functional unit called the B cell antigen receptor (BCR). Through a complex network of effector molecules, the BCR transforms environmental signals into biochemical reactions which are responsible for highly codified cellular responses affecting survival, proliferation, migration and terminal differentiation of B cells. Surface BCR expression is conserved in most types of B cell malignancies arising from mature B cells. This observation, together with genetic and biochemical evidence pointing to sustained BCR signaling in different types of B cell neoplasms represents the rationale for the current use of pharmacological inhibitors of BCR signaling to treat several forms of B lymphoproliferative disorders. Nevertheless, our understanding of how the BCR influences malignant B cell behavior remains poorly understood. In an attempt to fill this knowledge gap, we engineered a mouse model to monitor the effects of acute ablation of the BCR in highly-aggressive MYC-driven lymphomas. Inducible BCR ablation did not, per se, prevent the outgrowth of receptor-less MYC lymphoma cells both in vitro and in vivo. Instead, BCR loss weakened the fitness of the malignant B cells leading to the rapid elimination of BCR-less tumor cells in the presence of their BCR-expressing counterparts (Varano et al., 2017). Through the integration of data generated from genomics, metabolomics and bulk/single cell transcriptomics analyses, comparing BCR-deficient lymphoma cells to their proficient counterparts, we have started to elucidate the gene networks and metabolic pathways influenced by BCR expression that sustain competitive fitness of MYC-transformed lymphoma B cells. Data from CRISPR/Cas9-mediated disruption of candidate fitness genes in primary malignant B cells will be presented. In support of the findings in the mouse model, we will provide evidence that BCR-less malignant B cells are spontaneously generated during tumor progression in several forms of human B cell lymphoproliferative disorders, establishing a possible Achilles heel of anti-BCR therapies. Finally, we will report possible strategies enabling the clearance of BCR-less lymphoma cells, taking advantage of their acquired addiction to specific signaling and metabolic pathways. Our results shed light on the coordinated regulation of signaling and metabolism imposed on malignant B cells by BCR expression/signaling and provide indications for improved treatment options to fight several forms of mature B cell malignancies.
Reference:
Varano G, Raffel S, Sormani M, Zanardi F, Lonardi S, Zasada C, Perucho L, Petrocelli V, Haake A, Lee AK, Bugatti M, Paul U, Van Anken E, Pasqualucci L, Rabadan R, Siebert R, Kempa S, Ponzoni M, Facchetti F, Rajewsky K, Casola S. Nature. 2017; 546:302-306.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival1-3, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of ...activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival4-7. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies8,9. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3?) activity to support MYC-controlled gene expression. BCR- tumour cells exhibit increased GSK3? activity and are rescued from their competitive growth disadvantage by GSK3? inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3? activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR- tumour cells.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Purpose
To evaluate the concentrations of pro‐inflammatory cytokines in tear and aqueous humour of patients with primary open‐angle glaucoma (POAG), relative to healthy controls.
Method
Tear and ...aqueous humour samples were collected from 29 healthy controls and 27 POAG patients. Twenty‐seven inflammatory cytokines were analysed: interleukin (IL)‐1β, IL‐1ra, IL‐2, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, IL9, IL‐10, IL‐12, IL‐13, IL‐15, IL‐17, eotaxin, fibroblast growth factor (FGF) basic, granulocyte colony‐stimulating factor, granulocyte‐monocyte colony‐stimulating factor, interferon (IFN)‐γ, interferon gamma‐induced protein, monocyte chemo‐attractant protein‐1, macrophage inflammatory protein (MIP)‐1α, MIP‐1β, platelet‐derived growth factor, regulated on activation normal T cell expressed and secreted, tumour necrosis factor (TNF)‐α and vascular endothelial growth factor (VEGF).
Results
In tear samples of glaucoma patients, an increase in IL‐4, IL‐12, IL‐15, FGF‐basic and VEGF was observed, as well as a decrease in MIP‐1a relative to the control group (p < 0.05). IL‐5, IL‐12, IL‐15, IFN‐γ and MIP‐1a were significantly higher in aqueous humour of glaucoma eyes (p < 0.05). A poor correlation between cytokine levels in tear and aqueous humour was observed.
Conclusion
The different profiles of inflammatory marker expression of patients with POAG and healthy controls confirm the inflammatory activity of the pathology, indicating that some of them could be used as potential biomarkers of this disease.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Abstract
To assess the effectiveness and safety of the Preserflo Microshunt (PMS) implantation combined with cataract surgery in open-angle glaucoma (OAG) patients. Retrospective, open-label study ...conducted on insufficiently controlled OAG patients, who underwent a PMS implant procedure with mitomycin-C 0.2%, either alone or in combination with cataract surgery, and were followed for at least 12 months. Success was defined as an intraocular pressure (IOP) ≤ 18 mmHg and a reduction of at least 20% without (complete) or with (qualified) hypotensive medication. Fifty-eight eyes were included in the study, 35 eyes underwent PMS alone and 23 underwent PMS + Phaco. In the overall study sample, mean IOP was significantly lowered from 21.5 ± 3.3 mmHg at baseline to 14.6 ± 3.5 mmHg at month 12 (p < 0.0001). The IOP was significantly reduced in both groups; p < 0.0001 each, respectively. Ocular hypotensive medication was significantly reduced (p < 0.0001) in both groups. No significant differences were observed in IOP lowering or medication reduction between groups. At month 12, 62.1% eyes were considered as complete success and 82.8% eyes as qualified success. The most common adverse events were device close-to-endothelium, conjunctival fibrosis, and wound leakage. PMS, either alone or in combination with phacoemulsification, may be considered as a valuable option for treating OAG patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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