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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cell activation via CD3/Ti linked pathways results in the polymerization and reorganization of actin. However, little is known about the morphology and temporal appearance of filamentous actin (F-actin) after activation. Similarly, little is known about the relationship between F-actin and changes in cell shape or other parameters of activation, such as the appearance of proteins newly phosphorylated on tyrosine, that occur after stimulation via the CD3/Ti complex. Accordingly, we have characterized changes in cell shape and F-actin morphology occurring in the Jurkat T cell leukemia attached to the surface of culture vessels by immobilized anti-CD3 antibodies (OKT3, UCHT-1, SPV-T3b). These antibodies induced activation within 30 min as measured by increased protein tyrosine kinase activity and conversion of the proto-oncogene product, lck, from 56 kDa to 60 kDa (p56lck conversion), and after 12 to 96 h as measured by growth arrest and, in some experiments, IL-2 production. Activation was not seen when cells were attached to the substrates using antibodies directed to other cell surface proteins including CD71 (transferrin receptor), CD7, and CD11a (LFA-1), demonstrating the specificity of activation for immobilized anti-CD3 antibodies. Temporal changes in cell shape and F-actin morphology were characterized in Jurkat cells attached by immobilized anti-CD3 antibodies (stimulatory antibodies) and compared with the patterns obtained obtained in Jurkat cells attached by antibodies specific for the other markers (nonstimulatory antibodies). In these experiments, Jurkat cells were incubated with antibody-coated substrates for 1 to 30 min at 37 degrees C and actin rearrangements were visualized on fixed, detergent-permeabilized cells using rhodamine-conjugated phalloidin. Analysis of cell shape and F-actin morphology during the first 30 min of activation revealed a unique pattern that was observed only when cells were stimulated with anti-CD3 antibodies. Jurkat cells attached by either stimulatory or nonstimulatory antibodies reorganized their actin similarly after the first minute of culture, as characterized by the formation of small, F-actin rich pseudopods at the sites of attachment. After 5 min of culture in cells attached by stimulatory antibodies, the actin was polymerized into a dense collar rimming the inner edge of the cell. From 15 to 60 min, this collar was replaced by numerous F-actin rich, branched pseudopods. These branched pseudopods were larger and had longer microfilament bundles than their earlier counterparts. By contrast, in cells attached by nonstimulatory antibodies, the initial configuration was maintained for at least 60 min, except that a decrease in microfilament bundle length was noted.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Actin polymerization and pseudopod reorganization accompany anti-CD3-induced growth arrest in Jurkat T cells. 768 89

We investigated whether antisense oligodeoxynucleotides complementary to bcr/abl mRNA or protein kinase antagonists display antitumor activity on Ph1-positive leukemia cell lines. bcr/abl antisense oligomers showed inhibitory effects on the in vitro growth of Ph1-positive leukemia cell lines in liquid culture, and further displayed an inhibitory effect on transformed murine hematopoietic cells using transfection with a retroviral vector expressing P210bcr/abl oncoprotein. However, in vitro treatment with a bcr/abl antisense oligomer did not completely abolish the expression of bcr/abl mRNA and did not display the desired "killing effect" on Ph1-positive leukemia cells. On the other hand, investigation of the effect on Ph1-positive leukemia cells by various types of protein kinase antagonists revealed that herbimycin A, a protein tyrosine kinase antagonist, displays preferential and remarkable suppression of the growth of Ph1-positive leukemia cells and P210bcr/abl associated transformed cells by virtue of suppressing bcr/abl protein tyrosine kinase activity. These results may provide important future insights in developing a new category of antitumor therapy by targeting oncogene products.
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PMID:BCR/ABL oncoprotein-targeted antitumor activity of antisense oligodeoxynucleotides complementary to bcr/abl mRNA and herbimycin A, an antagonist of protein tyrosine kinase: inhibitory effects on in vitro growth of Ph1-positive leukemia cells and BCR/ABL oncoprotein-associated transformed cells. 769 3

We established IL-2-dependent T cells from an adult T-cell leukaemia (ATL) patient whose leukaemic cells changed from CD4 single-positive in the initial phase to double-negative (CD4- CD8-) at the time of exacerbation. The cells termed SO-4 were of ATL cell origin and showed the double-negative TCR alpha beta/CD3+ T-cell phenotype. SO-4 cells acquired CD4 antigen expression following stimulation with concanavalin A (ConA) or immobilized anti-CD3 antibody. The induction was inhibited by herbimycin A, an inhibitor of protein tyrosine kinase (PTK) activity. No CD4 mRNA was detectable in unstimulated SO-4 cells but a 3.0 kb signal specific for CD4 mRNA was detected after stimulation. These findings indicate that SO-4 cells return to their original phenotype (CD4 single-positive) by stimulation involving PTK. The results indicate that there is a pathway of phenotypic cycling between CD4 single-positive and double-negative T cells.
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PMID:Established IL-2-dependent double-negative (CD4- CD8-) TCR alpha beta/CD3+ ATL cells: induction of CD4 expression. 780 65

The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr-abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin a, which effectively reduced intracellular phosphorylation by bcr-abl tyrosine kinase, preferentially inhibited the growth of Ph1-positive leukemia cell lines. Injection of Ph1-positive and -negative leukemia cell lines into mice with severe combined immunodeficiency (SCID) resulted in the death of all mice due to leukemia, although the severity of illness varied according to the cell lines used. Administration of herbimycin A significantly enhanced the survival of mice inoculated with the Ph1-positive leukemia cell lines tested but barely affected the survival of mice inoculated with the Ph1-negative leukemia cell lines tested. These results suggest that herbimycin A and related compounds may be useful for the treatment of Ph1-positive leukemia. The disease that developed using the Ph1-positive leukemia cell line NALM-20 resembled human Ph1-positive acute lymphoid leukemia. There was an inverse relationship between the survival time of mice and the number of cells inoculated. The SCID mouse-NALM-20 human leukemia chimera would be a good experimental model for screening tyrosine kinase inhibitors as therapeutic agents against Ph1-positive leukemia.
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PMID:Treatment of Philadelphia-chromosome-positive human leukemia in SCID mouse model with herbimycin A, bcr-abl tyrosine kinase activity inhibitor. 786 Jan 43

Genistein is an inhibitor of the enzymes protein tyrosine kinase and topoisomerase-II. It induces G2-phase arrest in human Jurkat and murine P388 leukemia cells at concentrations at which it is also cytotoxic. The effects of genistein have been investigated on Jurkat and P388 leukemia sublines that manifest multidrug resistance. Cells that possess altered topoisomerase-II activity ("atypical" multidrug resistance) are resistant to both the G2 phase-arresting and cytotoxic effects of genistein. The ability of genistein to impede progression through the cell cycle and kill cells is similar to that of amsacrine, a classical topoisomerase-II poison. This result identifies topoisomerase-II rather than tyrosine kinase activity as the target of genistein-mediated cytotoxicity and G2-phase arrest.
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PMID:Comparison of the effects of genistein and amsacrine on leukemia cell proliferation. 791 50

Lymphoid cells transformed by Abelson murine leukemia virus have provided one of the classic models for study of early B-cell development and immunoglobulin rearrangement. Most of these cells have rearranged their heavy-chain locus but not their light chain genes, suggesting that an active v-abl protein interferes with this differentiation step. To test this hypothesis, light-chain gene structure was examined in pre-B cells transformed by temperature-sensitive mutants of the Abelson virus and in derivatives that survive at the nonpermissive temperature because they express a human BCL-2 gene. Our studies reveal that inactivation of the v-abl protein tyrosine kinase triggers high-frequency rearrangement of kappa and lambda light-chain genes. These events are accompanied by marked increases in the expression of RAG-1 and RAG-2 RNAs. These increases occur in the absence of protein synthesis but are dependent on inactivation of the v-abl protein tyrosine kinase. As documented in the accompanying paper (Klug et al., this issue), an active v-abl protein also suppresses the activity of NF-kappa B/rel and expression controlled by the kappa intron enhancer. Together these data demonstrate that the v-abl protein specifically interferes with light-chain gene rearrangement by suppressing at least two pathways essential for this stage of B-cell differentiation and suggest that tyrosine phosphorylation is important in regulating RAG gene expression.
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PMID:An active v-abl protein tyrosine kinase blocks immunoglobulin light-chain gene rearrangement. 792 59

The protein tyrosine kinase activity of the v-abl oncogene has been demonstrated to subvert the normal second messenger systems used by lymphoid cells for growth and differentiation. Transformation of bone marrow with the Abelson murine leukemia virus results in the appearance of B cell lineage cells arrested at the pre-B cell stage. Recent reports have characterized these cells expressing high v-abl kinase activity as deficient in detectable NF-kappaB DNA binding activity and low level RAG gene expression. These observations suggest that v-abl may be inhibiting the differentiation of B cells by blocking these two crucial elements in the maturation pathway.
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PMID:Arrested development: understanding v-abl. 794 72

Herbimycin A, a benzoquinoid ansamycin antibiotic, has been shown to reverse the oncogenic phenotype of p60v-src transformed cells because of the inhibition of src protein tyrosine kinase. We previously demonstrated that herbimycin A displayed antitumor activity on the in vitro growth of Philadelphia chromosome-positive leukemia cells and BCR/ABL-transfected murine hematopoietic FDC-P2 cells through the inhibition of BCR/ABL protein tyrosine kinase. In this study, the transformed FDC-P2 cells were demonstrated to be tumorigenic in syngeneic DBA/2 mice. The intraperitoneal (i.p.) injection of the transformed tumor cells into DBA/2 mice induced infiltrations of abdominal organs, and then all of the mice died within time periods proportional to the cell numbers of inoculation. In mice that received an i.p. inoculation with greater than 1 x 10(5) cells, in vivo administration of herbimycin A by i.p. injection inhibited tumor formation and significantly prolonged survival time, and further, in mice inoculated with 1 x 10(4) cells, herbimycin A completely suppressed the in vivo growth of transformant FDC-P2 cells and brought about a complete remission. The present study revealed the in vivo efficacy of herbimycin A in mice bearing BCR/ABL-transfected cells.
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PMID:In vivo antitumor activity of herbimycin A, a tyrosine kinase inhibitor, targeted against BCR/ABL oncoprotein in mice bearing BCR/ABL-transfected cells. 796 14

A member of the Src family of protein tyrosine kinases, Lyn is involved in the signaling pathways for cytokine or immunoglobulin-stimulated blood cells. Lyn is especially prominent in B-cell function. We have fine mapped LYN to chromosome 8q11-12 by fluorescence in situ hybridization. Of note, the gene for the pre-B cell growth factor, interleukin 7 (IL-7), has been mapped to 8q12-13. We show that IL-7 increases the protein tyrosine kinase activity of Lyn in the Daudi B-cell line. A third gene, HYRC, whose product may be involved in immunoglobulin rearrangement, has recently been localized to 8q11. We postulate that a lymphoid signaling region exists at 8q11-13.
Leukemia 1994 Nov
PMID:Localization of the human gene for Src-related protein tyrosine kinase LYN to chromosome 8q11-12: a lymphoid signaling cluster? 796 36

The T cell protein tyrosine kinase p56lck is implicated in thymic development and mitogenic activation of T lymphocytes, and is itself regulated by reversible tyrosine phosphorylation. When phenylarsine oxide (PAO), a membrane-permeable inhibitor of phosphotyrosine phosphatases, was added to Jurkat T leukemia or LSTRA thymoma cells, the phosphate content of p56lck increased rapidly. The sites of increased phosphorylation were mapped to Tyr-192, Tyr-394 and Tyr-505. Hyperphosphorylated p56lck displayed retarded mobility on SDS gels, unaltered or marginally increased cytoskeletal association, and its catalytic activity changed in a biphasic manner; during the first 10-20 min of PAO-treatment the activity increased and then it declined to very low values within 1-2 hr. Our data suggest that p56lck contains both positive and negative regulatory sites which are constantly dephosphorylated at an unexpectedly high rate by cellular phosphotyrosine phosphatases.
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PMID:Induction of hyperphosphorylation and activation of the p56lck protein tyrosine kinase by phenylarsine oxide, a phosphotyrosine phosphatase inhibitor. 799 41


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