Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been established that the BCR-ABL oncogene produced on the Philadelphia chromosome in human chronic myeloid leukemia(CML) directly causes leukemic transformation of multipotential progenitor cells. In order to study the molecular basis of this process, many convenient and useful biological assays have been found, including transformation of mouse bone marrow cells in primary culture and of Rat1 fibroblasts, cytokine-independent growth of dependent cell lines, retrovirus-mediated murine CML model, and transgenic mice model. New biological activities such as anti-apoptosis, anti-DNA repair, differentiation of ES cells may further give supportive explanations for clinical manifestation of CML. NOD/SCID transplantation model and conditional transgenic model may be the current best animal system by which to investigate cell dynamics in the most strict and natural circumstances.
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PMID:[Experimental systems in CML biology]. 1176 33

Chronic myelogenous leukemia (CML) is a hematopoietic malignant disease associated with expression of a chimeric BCR-ABL gene. We recently succeeded in designing a novel allosterically controllable ribozyme, the maxizyme (Tanabe et al. Biomacromolecules 2000, 1, 108-117; Kuwabara et al. Biomacromolecules 2001, 2, 788-799), that not only specifically cleaves BCR-ABL mRNA and induces apoptosis in cultured CML cells but also shows significant inhibition against the growth of an established BV173 cell line in a mouse model (Tanabe et al. Nature 2000, 406, 473-474). As an extension of our studies, we tested the maxizyme against primary CML cells in the same mouse model. The maxizyme under the control of a tRNA(Val) promoter showed significant inhibition against the growth of the primary bone marrow cells from a Japanese patient with CML. Specifically, to examine the applicability of the maxizyme in the treatment of CML, we assessed the antitumor effect of the maxizyme in murine models of CML. Fourteen weeks after the injection of primary CML cells into a NOD-SCID mouse, the bone marrow of the mouse was filled with primary CML cells as a result of diffuse leukemia. In marked contrast, when maxizyme-expressing primary CML cells were injected, the mouse remained disease-free. These results further strengthen our earlier suggestion that the maxizyme technology might provide a useful approach to the treatment of CML.
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PMID:Allosterically controllable maxizyme-mediated suppression of progression of leukemia in mice. 1177 96

Primitive human hematopoietic cells in granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood (MPB) are more difficult to transduce compared to cells from umbilical cord blood. Based on the hypothesis that MPB cells may require different stimulation for efficient retroviral infection, we compared several culture conditions known to induce cycling of primitive hematopoietic cells. MPB-derived CD34(+) cells were stimulated in the presence or absence of the murine fetal liver cell line AFT024 in trans-wells with G-CSF, stem cell factor (SCF), and thrombopoietin (TPO) (G/S/T; 100 ng/ml) or Flt3-L, SCF, interleukin (IL)-7, and TPO (F/S/7/T; 10-20 ng/ml), and transduced using a GaLV-pseudotyped retroviral vector expressing the enhanced green fluorescence protein (eGFP). Compared to cultures without stroma, the presence of AFT024 increased the number of transduced colony-forming cells (CFC) by 3.5-fold (with G/S/T), long-term culture-initiating cells (LTC-IC) by 4.6-fold (with F/S/7/T), and nonobese diabetic/severe immunodeficiency disease (NOD/SCID)-repopulating cells (SRC) by 6.8-fold (with F/S/7/T). Similar numbers of long-term culture-initiating cells (LTC-IC) and SRC could be transduced using AFT024-conditioned medium (AFT-CM) or a defined medium that had been supplemented with factors identified in AFT-CM. Finally, using our best condition based on transduction with the gibbon ape leukemia virus (GaLV)-pseudotyped vector, we demonstrate a 33-fold higher level of gene transfer (p < 0.001) in SRC using an RD114-pseudotyped vector. In summary, using an optimized protocol with low doses of cytokines, and transduction with an RD114 compared to a GaLV-pseudotyped retroviral vector, the overall number of transduced cells in NOD/SCID mice could be improved 144-fold, with a gene-transfer efficiency in SRC of 16.3% (13.3-19.9; n = 6).
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PMID:Optimization of gene transfer into primitive human hematopoietic cells of granulocyte-colony stimulating factor-mobilized peripheral blood using low-dose cytokines and comparison of a gibbon ape leukemia virus versus an RD114-pseudotyped retroviral vector. 1216 14

Adult human bone marrow (ABM) is an important source of hematopoietic stem cells for transplantation in the treatment of malignant and nonmalignant diseases. However, in contrast to the recent progress that has been achieved with umbilical cord blood, methods to expand ABM stem cells for therapeutic applications have been disappointing. In this study, we describe a novel culture method that uses human brain endothelial cells (HUBECs) and that supports the quantitative expansion of the most primitive measurable cell within the adult bone marrow compartment, the nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulating cell (SRC). Coculture of human ABM CD34(+) cells with brain endothelial cells for 7 days supported a 5.4-fold increase in CD34(+) cells, induced more than 95% of the CD34(+)CD38(-) subset to enter cell division, and produced progeny that engrafted NOD/SCID mice at significantly higher rates than fresh ABM CD34(+) cells. Using a limiting dilution analysis, we found the frequency of SRCs within fresh ABM CD34(+) cells to be 1 in 9.9 x 10(5) cells. Following HUBEC culture, the estimated frequency of SRCs increased to 1 in 2.4 x 10(5) cells. All mice that received transplants of HUBEC-cultured cells showed B-lymphoid and myeloid differentiation, indicating that a primitive hematopoietic cell was preserved during culture. Noncontact HUBEC cultures also maintained SRCs at a level comparable to contact HUBEC cultures, suggesting that cell-to-cell contact was not required. These data demonstrate that human brain endothelial cells possess a unique hematopoietic activity that increases the repopulating capacity of adult human bone marrow.
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PMID:Ex vivo culture with human brain endothelial cells increases the SCID-repopulating capacity of adult human bone marrow. 1239 35

Here we show that Janus kinase (JAK) 3 is an important molecular target for treatment of autoimmune insulin-dependent (type 1) diabetes mellitus. The rationally designed JAK3 inhibitor JANEX-1 exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes. Whereas 60% of vehicle-treated control NOD mice became diabetic by 25 weeks, the incidence of diabetes at 25 weeks was only 9% for NOD females treated with daily injections of JANEX-1 (100 mg/kg/day) from Week 10 through Week 25 (P = 0.007). Furthermore, JANEX-1 prevented the development of insulitis and diabetes in NOD-scid/scid females after adoptive transfer of splenocytes from diabetic NOD females. Chemical inhibitors such as JANEX-1 may provide the basis for effective treatment modalities against human type 1 diabetes. To our knowledge, this is the first report of the immunosuppressive activity of a JAK3 inhibitor in the context of an autoimmune disease.
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PMID:Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice. 1270 8

Severe combined immunodeficient (SCID)-repopulating cells (termed SRC) with lymphohaematopoietic differentiation potential reside at an extremely low frequency in unmobilised adult human peripheral blood. Recently, an ex vivo method of increasing the relative numbers of at least four distinct human stem cell classes, that include CD34+ haematopoietic progenitor cells, in mononuclear cells (MNC) obtained from unmobilised adult human peripheral blood has been described. This process is triggered by a monoclonal antibody (mAb) against the human monomorphic region of the beta chain of HLA-DP, DQ and DR (clone CR3/43). Herein, we assess the ability of human male donor-derived MNC, following ex vivo culturing for 3 hr in haematopoietic-conducive conditions (HCC) (3-hr MNC/HCC), to form SRC in female non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. All 3-hr MNC/HCC-recipient animals exhibited significant levels (> 0.5%) of human cell engraftment in the bone marrow, thymus and spleen when compared to animals receiving MNC cultured in the absence of CR3/43. Phenotypic characterisation of the bone marrow cell populations of engrafted mice demonstrated significant levels of human lymphohaematopoietic cell lineages, comprised of T lymphocytes, monocytes, erythrocytes and megakaryocytes, including platelets. In addition, significant levels of clonogenic human CD34+ cells were also detected by in vitro surrogate assay. The thymi of engrafted animals contained maturating human thymocytes, while the spleen consisted mainly of T lymphocytes. Fluorescence in situ hybridisation (FISH) further identified the presence of human male X and Y chromosomes at engrafted sites, whilst the human origin of the cells was confirmed by a specific PCR assay for the human Cart-1 gene. In conclusion, the conversion of MNC to SRC in response to treatment with CR3/43 for 3 hr could have far-reaching clinical implications especially where time and donor-histocompatibility are limiting factors.
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PMID:SCID repopulating cells derived from unmobilised adult human peripheral blood. 1474 Oct 77

In this study, we describe the successful use of a gene transfer approach to demonstrate the ability of forced BCR-ABL expression to deregulate the growth and differentiation of primitive naive human hematopoietic cells after their transplantation into immunodeficient mice. Human CD34+ cord blood cells were exposed to an MSCV retrovirus containing a BCR-ABL-IRES-GFP (P210) cassette and then injected immediately into sublethally irradiated nonobese diabetic-severe combined immunodeficiency (NOD/SCID) or NOD/SCID-beta2microglobulin-/- mice. P210- and control-transduced (GFP+) human hematopoietic cells were produced in the bone marrow of the mice at similar levels until termination of the experiments 5-6 months later. However, the P210-transduced cells produced a markedly different spectrum of progeny, with an increased ratio of myeloid to B-lymphoid cells and a frequently prolonged increase in erythroid and megakaryocytic cells. After 5 months, several of the mice transplanted with P210-transduced cells developed an increased WBC count and/or splenomegaly due to an expansion of the human GFP+ population. These findings demonstrate that forced expression of BCR-ABL in primitive transplantable human hematopoietic cells is sufficient to cause a rapid and persistent deregulation of their growth and differentiation in vivo with occasional evidence after several months of progression to an early stage of disease.
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PMID:BCR-ABL-transduced human cord blood cells produce abnormal populations in immunodeficient mice. 1567 17

Although the dioxin receptor, the aryl hydrocarbon receptor (AhR), is considered a major regulator of xenobiotic-induced carcinogenesis, its role in tumor formation in the absence of xenobiotics is still largely unknown. Trying to address this question, we have produced immortalized cell lines from wild-type (T-FGM-AhR+/+) and mutant (T-FGM-AhR-/-) mouse mammary fibroblasts by stable co-transfection with the simian virus 40 (SV-40) large T antigen and proto-oncogenic c-H-Ras. Both cell lines had a myofibroblast phenotype and similar proliferation, doubling time, SV-40 and c-H-Ras expression and activity, and cell cycle distribution. AhR+/+ and AhR-/- cells were also equally able to support growth factor- and anchorage-independent proliferation. However, the ability of T-FGM-AhR-/- to induce subcutaneous tumors (leimyosarcomas) in NOD/SCID-immunodeficient mice was close to 4-fold lower than T-FGM-AhR+/+. In culture, T-FGM-AhR-/- had diminished migration in collagen-I and decreased lamellipodia formation. VEGFR-1/Flt-1, a VEGF receptor that regulates cell migration and blood vessel formation, was also down-regulated in AhR-/- cells. Signaling through the ERK-FAK-PKB/AKT-Rac-1 pathway, which contributes to cell motility and invasion, was also significantly inhibited in T-FGM-AhR-/-. Thus, the lower tumorigenic potential of T-FGM-AhR-/- could result from a compromised adaptability of these cells to the in vivo microenvironment, possibly because of an impaired ability to migrate and to respond to angiogenesis.
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PMID:Immortalized mouse mammary fibroblasts lacking dioxin receptor have impaired tumorigenicity in a subcutaneous mouse xenograft model. 1594 50

IFN-gamma promotes the development of lymphocytic spontaneous autoimmune thyroiditis (L-SAT) in NOD.H-2h4 mice and inhibits the development of thyrocyte hyperplasia and proliferation (TEC H/P). The precise mechanisms by which IFN-gamma promotes L-SAT and inhibits TEC H/P are unknown. To determine whether responsiveness of lymphocytes or thyrocytes to IFN-gamma is important for the development of these lesions, IFN-gammaR-/- mice, which develop TEC H/P similar to IFN-gamma-/- mice, were used as recipients for adoptive cell transfer. Wild-type (WT) splenocytes or bone marrow induced L-SAT and inhibited TEC H/P in IFN-gamma-/-, but not IFN-gammaR-/- recipients. IFN-gammaR-/- recipients of WT cells developed severe TEC H/P, but did not develop L-SAT, suggesting that thyrocytes responding to IFN-gamma are important for inhibition of TEC H/P. Unexpectedly, IFN-gammaR-/- splenocytes or bone marrow did not induce L-SAT in IFN-gamma-/- or WT mice even though IFN-gammaR-/- lymphocyte donors produced as much IFN-gamma as lymphocytes from WT donors, and thyrocytes could respond to IFN-gamma. Real-time PCR indicated that recipients of IFN-gammaR-/- bone marrow expressed less mRNA for IFN-gamma-inducible chemokines compared with recipients of WT bone marrow. This might limit the migration of IFN-gammaR-/- lymphocytes to thyroids. Few IFN-gammaR-/- lymphocytes infiltrated thyroids even in the presence of WT lymphocytes, suggesting that lymphocytes unable to respond to IFN-gamma are not induced to migrate to thyroids. These results suggest that thyrocytes must be able to respond to IFN-gamma for the development of L-SAT and inhibition of TEC H/P, and lymphocytes must be able to respond to IFN-gamma to induce L-SAT.
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PMID:Thyrocytes responding to IFN-gamma are essential for development of lymphocytic spontaneous autoimmune thyroiditis and inhibition of thyrocyte hyperplasia. 1639 17

Activation of JAK2 by chromosomal translocation or point mutation is a recurrent event in hematopoietic malignancies, including acute leukemias and myeloproliferative disorders. Although the effects of activated JAK2 signaling have been examined in cell lines and murine models, the functional consequences of deregulated JAK2 in the context of human hematopoietic cells are currently unknown. Here we report that expression of TEL-JAK2, a constitutively active variant of the JAK2 kinase, in lineage-depleted human umbilical cord blood cells results in erythropoietin-independent erythroid differentiation in vitro and induces the rapid development of myelofibrosis in an in vivo NOD/SCID xenotransplantation assay. These studies provide functional evidence that activated JAK2 signaling in primitive human hematopoietic cells is sufficient to drive key processes implicated in the pathophysiology of polycythemia vera and idiopathic myelofibrosis. Furthermore, they describe an in vivo model of myelofibrosis initiated with primary cells, highlighting the utility of the NOD/SCID xenotransplant system for the development of experimental models of human hematopoietic malignancies.
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PMID:Expression of TEL-JAK2 in primary human hematopoietic cells drives erythropoietin-independent erythropoiesis and induces myelofibrosis in vivo. 1707 40


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