The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells

Members of the Runx family of transcriptional regulators are required for the appropriate expression of CD4 and CD8 at discrete stages of T cell development. The roles of these factors in other aspects of T cell development are unknown. We used a strategy to conditionally inactivate the genes encoding Runx1 or Runx3 at different stages of thymocyte development, demonstrating that Runx1 regulates the transitions of developing thymocytes from the CD4−CD8− double-negative stage to the CD4+CD8+ double-positive (DP) stage and from the DP stage to the mature single-positive stage. Runx1 and Runx3 deficiencies caused marked reductions in mature thymocytes and T cells of the CD4+ helper and CD8+ cytotoxic T cell lineages, respectively. Runx1-deficient CD4+ T cells had markedly reduced expression of the interleukin 7 receptor and exhibited shorter survival. In addition, inactivation of both Runx1 and Runx3 at the DP stages resulted in a severe block in development of CD8+ mature thymocytes. These results indicate that Runx proteins have important roles at multiple stages of T cell development and in the homeostasis of mature T cells

Repression of interleukin-4 in T helper type 1 cells by Runx/Cbfβ binding to the Il4 silencer

Interferon γ (IFNγ) is the hallmark cytokine produced by T helper type 1 (Th1) cells, whereas interleukin (IL)-4 is the hallmark cytokine produced by Th2 cells. Although previous studies have revealed the roles of cytokine signaling and of transcription factors during differentiation of Th1 or Th2 cells, it is unclear how the exclusive expression pattern of each hallmark cytokine is established. The DNaseI hypersensitivity site IV within the mouse Il4 locus plays an important role in the repression of Il4 expression in Th1 cells, and it has been named the Il4 silencer. Using Cbfβ- or Runx3-deficient T cells, we show that loss of Runx complex function results in derepression of IL-4 in Th1 cells. Binding of Runx complexes to the Il4 silencer was detected in naive CD4+ T cells and Th1 cells, but not in Th2 cells. Furthermore, enforced expression of GATA-3 in Th1 cells inhibited binding of Runx complexes to the Il4 silencer. Interestingly, T cell–specific inactivation of the Cbfβ gene in mice led to elevated serum immunoglobulin E and airway infiltration. These results demonstrate critical roles of Runx complexes in regulating immune responses, at least in part, through the repression of the Il4 gene

Small Cell Carcinoma of the Ureter with Malignant Lymphoma: Case Report and Literature Review

A 78-year-old man was referred to our hospital for gross hematuria. Ultrasonography and magnetic resonance urography revealed tumor in the right lower ureter. Computed tomography revealed right cervical lymph node swelling and pathological diagnosis was diffuse large B-cell lymphoma. Right nephroureterectomy was performed and pathologic examination revealed small cell carcinoma of the ureter with a small urothelial cell carcinoma component. As the patient had concomitant other malignancies, additional systemic chemotherapy was not performed. As of 3 months after operation, postoperative course has been uneventful. Only 11 cases of primary small cell carcinoma of the ureter have been described

Runx proteins regulate Foxp3 expression

Runx proteins are essential for hematopoiesis and play an important role in T cell development by regulating key target genes, such as CD4 and CD8 as well as lymphokine genes, during the specialization of naive CD4 T cells into distinct T helper subsets. In regulatory T (T reg) cells, the signature transcription factor Foxp3 interacts with and modulates the function of several other DNA binding proteins, including Runx family members, at the protein level. We show that Runx proteins also regulate the initiation and the maintenance of Foxp3 gene expression in CD4 T cells. Full-length Runx promoted the de novo expression of Foxp3 during inducible T reg cell differentiation, whereas the isolated dominant-negative Runt DNA binding domain antagonized de novo Foxp3 expression. Foxp3 expression in natural T reg cells remained dependent on Runx proteins and correlated with the binding of Runx/core-binding factor β to regulatory elements within the Foxp3 locus. Our data show that Runx and Foxp3 are components of a feed-forward loop in which Runx proteins contribute to the expression of Foxp3 and cooperate with Foxp3 proteins to regulate the expression of downstream target genes

Transcriptional reprogramming of mature CD4 + helper T cells generates distinct MHC class II- restricted cytotoxic T lymphocytes

2 8 1 CD4 + T cells are commonly classified as 'helper' T cells on the basis of their roles in providing help to promote or dampen cellular and humoral immune responses. In contrast, CD8αβ + cytotoxic T lympho cytes (CTLs) provide direct protective immunity by killing infected or transformed cells. The helper T cell program is initially induced during thymic development, during which thymocytes expressing a major histocompatibility complex (MHC) class II-reactive T cell antigen receptor (TCR) develop into the CD4 + helper T cell lineage, whereas thymocytes with specificity for MHC class I differentiate into the CD8 + CTL lineage. The functional programming, which coincides with but does not depend on the MHC restriction or expression of the coreceptor CD4 or CD8αβ, is controlled by the action and counter action of key transcription factors. Together with Tox and GATA3, the helper T cell transcription factor ThPOK (cKrox; encoded by Zbtb7b (called 'Thpok' here)) first induces the CD4 + helper T cell fate and prevents thymocytes from differentiating into CD8 + CTLs 1-6 . Runx3, a member of the Runx family of transcription factors, has the opposite effect and terminates CD4 expression while promoting differentiation into the CTL lineage That lineage separation, however, is not all encompassing, and reports have repeatedly indicated the presence of CD4 + T cells with cytolytic functions in various species, including humans and rodent

Relationship between PDGFR expression and the response to pazopanib in intimal sarcoma of the pulmonary artery: A case report

Intimal sarcoma of the pulmonary artery (PAIS) is a rare disease with a poor prognosis. Pazopanib, which has been indicated in metastatic non-adipocytic soft-tissue sarcomas and is expected to be active in PAIS, is a multi-kinase inhibitor that targets the tyrosine kinase activity of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor. The present study reports findings related to two cases of PAIS with PDGF and VEGF expression following treatment with pazopanib. A case with a moderate to strong expression of PDGFR-α and -β presented a long-term stable disease when treated with pazopanib (progression-free survival, 5.8 months). In a second case with a weak expression of PDGFR-α and -β, the disease progressed rapidly on pazopanib (progression-free survival, 1.1 months). VEGFR-2 was not expressed in the tumors of both cases. The level of PDGFR expression in the tumor tissue may therefore be predictive of pazopanib efficacy

Design and synthesis of a novel class of CK2 inhibitors: application of copper- and gold-catalysed cascade reactions for fused nitrogen heterocycles.

Two classes of fused nitrogen heterocycles were designed as CK2 inhibitor candidates on the basis of previous structure-activity relationship (SAR) studies. Various dipyrrolo[3, 2-b:2', 3'-e]pyridine and benzo[g]indazole derivatives were prepared using transition-metal-catalysed cascade and/or multicomponent reactions. Biological evaluation of these candidates revealed that benzo[g]indazole is a promising scaffold for potent CK2 inhibitors. The inhibitory activities on cell proliferation of these potent CK2 inhibitors are also presented