Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Foxp3 is a master gene of Treg cells, a novel subset of CD4(+) T cells primarily expressing CD25. We describe here different features in Foxp3 expression profile between normal and leukemic CD4(+)CD25(+) T cells, using peripheral blood samples from healthy controls (HCs), human T-cell leukemia virus type-1 (HTLV-1)-infected asymptomatic carriers (ACs), patients with adult T-cell leukemia (ATL), and various hematopoietic cell lines. The majority of CD4(+)CD25(+) T cells in HCs were positive for Foxp3, but not all CD4(+)CD25(+) T cells in ACs were positive, indicating that Foxp3 expression is not always linked to CD25 expression in normal T cells. Leukemic (ATL) T cells constitutively expressing CD25 were characteristic of heterogeneous Foxp3 expression, such as intra- and inter-case heterogeneity in intensity, inconsistency with CD25 expression, and a discrepancy in the mRNA and its protein expression. Surprisingly, a discernible amount of Foxp3 mRNA was detectable even in most cell lines without CD25 expression, a small fraction of which was positive for the Foxp3 proteins. The subcellular localization of Foxp3 in HTLV-1-infected cell lines was mainly cytoplasmic, different from that of primary ATL cells. These findings indicate that Foxp3 has two facets: essential Treg identity and molecular mimicry secondary to tumorigenesis. Conclusively, Foxp3 in normal T cells, but not mRNA, is basically potent at discriminating a subset of Treg cells from CD25(+) T-cell populations, whereas the modulation of Foxp3 expression in leukemic T cells could be implicated in oncogenesis and has a potentially useful clinical role.
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PMID:Foxp3 expression on normal and leukemic CD4+CD25+ T cells implicated in human T-cell leukemia virus type-1 is inconsistent with Treg cells. 1851 Jun 97

Angiogenesis is thought to be involved in the development of acute leukemia (AL). We investigated whether bone marrow stromal cells (BMSCs) derived from stem cells might be responsible for the increase in microvascular density (MVD), and compared 13 bone marrow samples from AL patients with 23 samples from patients in complete remission (controls). We demonstrated that AL-derived BMSC secreted more insulin growth factor-1 (IGF-1) and SDF-1alpha than controls. In addition, in contrast to normal adherent BMSCs, adherent BMSCs derived from CD133+/CD34+ stem cells from AL patients were able to form capillary-like structures ('vasculogenic mimicry') on Matrigel. The increase in vasculogenic mimicry occurred through PI3 kinase and rho GTPase pathway as inhibitors of these signaling pathways (wortmannin and GGTI-298, respectively) were able to reduce or prevent capillary tube formation. In normal BMSC, addition of exogenous IGF-1 generated capillary-like tubes through the same pathway as observed spontaneously in AL-derived BMSC. The involvement of IGF-1 in the mimicry process was confirmed by the addition of a neutralizing antibody against IGF-1R or a IGF-1R pathway inhibitor (picropodophyllin). In conclusion, AL-derived BMSC present functional abnormalities that may explain the increase in MVD in the bone marrow of AL patients.
Leukemia 2009 Jun
PMID:Vasculogenic mimicry of acute leukemic bone marrow stromal cells. 1934 2

The pathogenic mechanisms of intraocular inflammation had not been well studied until Wacker and his colleagues found retinal soluble antigen (S antigen) and established experimental autoimmune uveitis (EAU), an animal model for autoimmune uveitis. Using this animal model, great progress in understanding the immunopathogenic mechanisms of uveitis was achieved not only in EAU, but also in many inflammatory disorders in humans. Intraocular inflammation is mediated by activated CD4+ T cells. However, the eye has a unique regional immune system which protects intraocular tissues from these pathogenic activated CD4+ T cells and contributes to the homeostasis of the intraocular microenvironment. In the present review article, the role of T cells in immunopathogenic mechanisms of ocular inflammatory disorders as well as in the regional defense system of the eye is highlighted. 1. Immunopathogenic mechanisms of EAU: Experiments using athymic nude rats as well as adoptive transfer of EAU by S-antigen-sensitized T lymphocytes into naive Lewis rats disclosed that T lymphocytes, particularly CD4+ T lymphocytes, play a central role in the immunopathogenic mechanisms of EAU. In addition, immunopharmacological studies showing the intense effects of cyclosporine on EAU with selective immunosuppression to T lymphocytes allowed us to use clinically the agent to treat patients with refractory uveitis of non-infectious origins, such as Behcet's disease. 2. Immunopathogenic mechanisms of uveitis in human: Two clinical uveitis entities commonly seen in Japan, i. e. Vogt-Koyanagi-Harada (VKH) disease and human T-cell leukemia virus type 1 (HTLV-1) uveitis, were studied for their pathogenic mechanisms. (1) VKH disease: We established T cell clones from infiltrating cells in the eyes of VKH patients using limiting dilution methods. CD4+ T cell clones from VKH disease, but not from other uveitis entities, responded to tyrosinase, a melanocyte-associated antigen, and produced inflammatory cytokines, and the response was specific to tyrosinase. Furthermore, DataBank analysis disclosed that tyrosinase had a structural homology with an exogenous antigen, a glycoprotein peptide of cytomegalovirus (CMV). CD4+ T lymphocytes from VKH patients, but not from other diseases, which responded to both tyrosinase and CMV peptide. This indicates that molecular mimicry between CMV peptide and tyrosinase plays an important role in the immunopathogenic mechanisms by which CD4+ T lymphocytes are sensitized to autoantigen of tyrosinase and cause inflammation in VKH disease. (2) HTLV-1 uveitis: Similar to adult T cell leukemia and HTLV-1 associated myelopathy, uveitis in asymptomatic carriers of HTLV-1, prevalent in southern Kyushu, is a distinct clinical entity associated with HTLV-1, a human retrovirus. We analyzed ocular infiltrating cells and found that (a) HTLV-1-infected CD4+ T lymphocytes were significantly accumulated in the eye, and (b) HTLV-1-infected CD4+ T lymphocytes produced a large amount of various inflammatory cytokines. Thus, CD4+ T lymphocytes play a central role in the pathogenic mechanisms of HTLV-1 uveitis. 3. Regional defense system of the eye: As described above, CD4+ T lymphocytes made active by either autoantigens or exogenous pathogens, enter the eye and cause inflammatory responses. However, the eye is known to be an immune privileged site. We focused on ocular pigment epithelial cells because they form a blood-ocular barrier, and they may protect the eye immunologically from infiltrating inflammatory cells. Our major findings by in vitro experiments in mice are (a) ocular pigment epithelial cells have the capacity to suppress activated CD4+ T lymphocytes; (b) the mode of action of iris pigment epithelial cells (IPE) and retinal pigment epithelial cells (RPE) are different: T lymphocyte suppression by IPE requires cell-to-cell contact, whereas suppression by RPE requires soluble factors, but not cell-to-cell contact; (c) both IPE and RPE have the capacity to generate regulatory T cells(Treg), thereby enhancing immune regulation in the eye. In conclusion, CD4+ T lymphocytes activated by either autoantigens or infectious agents play a central role in the pathogenic mechanisms of ocular inflammation, and ocular resident cells such as IPE and RPE suppress the pathogenic activated CD4+ T lymphocytes, thereby contributing to homeostasis of the eye.
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PMID:[Intraocular inflammation and homeostasis of the eye]. 1934 83

Acute myeloid leukaemia (AML) is a cancer of haematopoietic cells that develops in three-dimensional (3-D) bone marrow niches in vivo. The study of AML has been hampered by lack of appropriate ex vivo models that mimic this microenvironment. We hypothesised that fabrication and optimisation of suitable biomimetic scaffolds for culturing leukaemic cells ex vivo might facilitate the study of AML in its native 3-D niche. We evaluated the growth of three leukaemia subtype-specific cell lines, K-562, HL60 and Kasumi-6, on highly porous scaffolds fabricated from biodegradable and non-biodegradable polymeric materials, such as poly (L-lactic-co-glycolic acid) (PLGA), polyurethane (PU), poly (methyl-methacrylate), poly (D, L-lactade), poly (caprolactone), and polystyrene. Our results show that PLGA and PU supported the best seeding efficiency and leukaemic growth. Furthermore, the PLGA and PU scaffolds were coated with extracellular matrix (ECM) proteins, collagen type I (62.5 or 125 microg/ml) and fibronectin (25 or 50 microg/ml) to provide biorecognition signals. The 3 leukaemia subtype-specific lines grew best on PU scaffolds coated with 62.5 microg/ml collagen type I over 6 weeks in the absence of exogenous growth factors. In conclusion, PU-collagen scaffolds may provide a practical model to study the biology and treatment of primary AML in an ex vivo mimicry.
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PMID:The development of a three-dimensional scaffold for ex vivo biomimicry of human acute myeloid leukaemia. 2001 43

Hematopoietic stem cells require a unique microenvironment in order to sustain blood cell formation; the bone marrow (BM) is a complex three-dimensional (3D) tissue wherein hematopoiesis is regulated by spatially organized cellular microenvironments termed niches. The organization of the BM niches is critical for the function or dysfunction of normal or malignant BM(5). Therefore a better understanding of the in vivo microenvironment using an ex vivo mimicry would help us elucidate the molecular, cellular and microenvironmental determinants of leukemogenesis. Currently, hematopoietic cells are cultured in vitro in two-dimensional (2D) tissue culture flasks/well-plates requiring either co-culture with allogenic or xenogenic stromal cells or addition of exogenous cytokines. These conditions are artificial and differ from the in vivo microenvironment in that they lack the 3D cellular niches and expose the cells to abnormally high cytokine concentrations which can result in differentiation and loss of pluripotency. Herein, we present a novel 3D bone marrow culture system that simulates the in vivo 3D growth environment and supports multilineage hematopoiesis in the absence of exogenous growth factors. The highly porous scaffold used in this system made of polyurethane (PU), facilitates high-density cell growth across a higher specific surface area than the conventional monolayer culture in 2D. Our work has indicated that this model supported the growth of human cord blood (CB) mononuclear cells (MNC) and primary leukemic cells in the absence of exogenous cytokines. This novel 3D mimicry provides a viable platform for the development of a human experimental model to study hematopoiesis and to explore novel treatments for leukemia.
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PMID:Ex vivo mimicry of normal and abnormal human hematopoiesis. 2252 32

Natural products that inhibit the proteasome have been fruitful starting points for the development of drug candidates. Those of the syringolin family have been underexploited in this context. Using the published model for substrate mimicry by the syringolins and knowledge about the substrate preferences of the proteolytic subunits of the human proteasome, we have designed, synthesized, and evaluated syringolin analogs. As some of our analogs inhibit the activity of the proteasome with second-order rate constants 5-fold greater than that of the methyl ester of syringolin B, we conclude that the substrate mimicry model for the syringolins is valid. The improvements in in vitro potency and the activities of particular analogs against leukemia cell lines are strong bases for further development of the syringolins as anti-cancer drugs.
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PMID:Substrate-guided optimization of the syringolins yields potent proteasome inhibitors with activity against leukemia cell lines. 2629 13


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