Project description:Plasmablastic lymphoma is an aggressive B-cell lymphoma with an immunoblastic/large cell morphology anda plasmacytic differentiation. The differential diagnosis with Burkitt lymphoma, plasma cell myeloma and some variants of diffuse large B-cell lymphoma may be challenging due to the overlapping morphological, genetic and immunophenotypic features. Furthermore, the profile of chromosomal alterations is not well known.
Project description:Here we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor. We use five classical Hodgkin lymphoma cell lines: L428, L1236, L540, KMH2, L591
Project description:Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.
Project description:Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.
Project description:Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.
Project description:Although the JAK/STAT pathway regulates numerous processes in vertebrates and invertebrates through modulating transcription, its functionally-relevant transcriptional targets remain largely unknown. With one jak and one stat (stat92E), Drosophila provides a powerful system for finding new JAK/STAT target genes. Genome-wide expression profiling on eye discs in which Stat92E is hyperactivated, revealed 584 differentially-regulated genes, including known targets domeless, socs36E and wingless. Other differentially-regulated genes (chinmo, lama, Mo25, Imp-L2, Serrate, Delta) were validated and may represent new Stat92E targets. Genetic experiments revealed that Stat92E cell-autonomously represses Serrate, which encodes a Notch ligand. Loss of Stat92E led to de-repression of Serrate in the dorsal eye, resulting in ectopic Notch signaling and aberrant eye growth there. Thus, our micro-array documents a new Stat92E target gene and a previously-unidentified inhibitory action of Stat92E on Notch signaling. These data suggest that this study will be a useful resource for the identification of additional Stat92E targets. Identification of the JAK/STAT pathway target genes in the Drosophila eye disc Keywords: Genotype comparison Gene expression profiles from five biological replicates of eye discs with yw (control) and GMR-upd (overexpressing JAK/STAT ligand unpaired) were compared using genome wide mRNA expression profiling by Affymetrix genechip arrays (Drosophila 2.0) and key targets were validated by clonal analysis, in situ hybridization, immunohistochemical staining and quantitative real-time PCR.
Project description:Chronically activated JAK/STAT signaling leads to several lung diseases, including lung cancer, asthma, and chronic obstructive pulmonary disease. We used the fruit fly Drosophila melanogaster to elucidate the molecular processes which transform elevated JAK/STAT signaling in airway epithelial cells into pathology.
Project description:NFIC1, the longest isoform of NFIC, is essential for the regulation on spatiotemporal expressions of drug-metabolizing genes in liver. However, the role of NFIC1 in breast cancer is not clear. Here we showed that increased expression of NFIC1 suppressed the migration and invasion of MCF-7 cells. The activation of interferon-associated Jak-STAT pathway was enhanced with NFIC1 overexpression. NFIC1 overexpression upregulated the expression of IFNB1, IFNL1, IFNL2 and IFNL3. Treatment with Jak-STAT pathway inhibitors, Filgotinib or Ruxolitinib, reversed the suppressive effects of NFIC1 overexpression on migration and invasion. In addition, we found that MX1 and MX2 were the target genes of NFIC1- activated Jak-STAT pathway, which mediated the migration and invasion of MCF-7 cells. These results demonstrated that NFIC1 inhibited the migration and invasion in MCF-7 cells through interferon mediated activation of Jak-STAT pathway, indicating that Jak-STAT pathway might be a potential therapeutic target for preventing breast cancer metastasis.