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

Preincubation of tumor cells with actinomycin D (Act D) rendered various murine and human lines susceptible to killing by unstimulated human peripheral blood mononuclear cells (PBM) in a 6-hr 51Cr-release assay. The murine WEHI 164 sarcoma was selected for analysis of drug-dependent cellular cytotoxicity (DDCC) because high levels of killing were detected with this tumor, and it was considerably resistant to natural killer (NK) cell activity. Optimal conditions for induction of susceptibility to lysis included a 3-hr preincubation with 1 microgram/ml Act D. Effector cells of cytotoxicity against Act D-treated WEHI 164 cells were plastic adherent (greater than 85% monocytes). Cells nonadherent to plastic and nylon wool (less than or equal to 1% monocytes) had no appreciable DDCC activity. In contrast NK activity against K562 cells was mediated by nonadherent cells. When PBM were fractionated on a one step discontinuous gradient of Percoll designed to enrich for monocytes (greater than 90% pure), DDCC activity was found in the monocyte fraction, and the lymphoid cell-enriched fraction had no cytotoxicity against Act D-treated WEHI 164 cells. In contrast, NK activity against K562 was recovered with lymphoid cells, and monocytes had no NK cytotoxicity. Upon fractionation on a six step Percoll gradient designed to enrich for large granular lymphocytes (LGL), the denser lymphocytes (fraction 4-6) and the less dense LGL with NK activity (fraction 2-3) had no cytotoxicity against Act D-treated WEHI 164 sarcoma cells. DDCC activity sedimented in fraction 1 in association with monocytes. PBM were fractionated according to monoclonal antibody-defined surface markers by using a fluorescence-activated cell sorter. Effector cells of DDCC were positive for monocyte markers (Mo2, UCHM1) and were negative for NK cell (B73.1, HNK1), T cell (T11), and B cell (Leu-10) markers. Macrophages obtained by culturing blood monocytes in vitro for 5 to 10 days had DDCC activity. Similarly, peritoneal and bronchoalveolar macrophages had considerable cytotoxicity against Act D-treated target cells, whereas minimal or no NK activity was found at these anatomic sites. Cells of human or murine origin, preincubated with Act D for 3 hr, were heterogeneous in their susceptibility to monocyte killing in a 6-hr 51Cr-release assay. High levels of cytotoxicity were observed with the murine WEHI 164 sarcoma and 3T3 "fibroblast" line and with the human CEM leukemia. Monocytes were weakly (but significantly) cytotoxic against the ALAB breast carcinoma (human) and the 8387 sarcoma (human).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Rapid killing of actinomycin D-treated tumor cells by human mononuclear cells. I. Effectors belong to the monocyte-macrophage lineage. 669 Jun 24

Somatostatin (SS) is a 14 amino acid peptide which is secreted by the hypothalamus and the pancreatic islets. It expresses antiproliferative activity in various organ systems, experiments have suggested effects of SS on hematopoietic cells. Here we present investigations regarding the effect of SS and its analog SMS 201-995 (SMS) on the in vitro proliferation of acute lymphoblastic leukemia (ALL; n = 7 cases), acute myeloid leukemia (AML; n = 21 cases) and chronic lymphocytic leukemia (CLL; n = 2 cases). Both SS and SMS inhibited spontaneous leukemic cell growth in approximately 1/3 of cases (i.e. 7/19). G-CSF stimulated AML cells were inhibited by SMS in 11/21 cases. AML cell proliferation induced by IL-3 or GM-CSF was suppressed in only 3/21 and 6/21 cases, respectively. In ALL cells, IL-7-induced proliferation was suppressed by SMS in 3/7 cases. The effect of SMS seemed to depend on the type of the hematopoietic growth factor, and on their concentrations. In fact, high concentrations of G-CSF could override SMS blocking completely. Colony formation by normal marrow progenitors and DNA synthesis by HL-60 and T11/65 leukemic cell lines were not affected by SMS. In conclusion, somatostatin may act as a negative regulator of the proliferative activity of human leukemia.
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PMID:Somatostatin and its cyclic octapeptide analog SMS 201-995 as inhibitors of proliferation of human acute lymphoblastic and acute myeloid leukemia. 750 Jun 46

The mitogenic activity of human T-cell leukemia virus type I (HTLV-I) is triggering the proliferation of human resting T lymphocytes through the induction of the interleukin-2 (IL-2)/IL-2 receptor autocrine loop. This HTLV-I-induced proliferation was found to be mainly mediated by the CD2 T-cell antigen, which is first expressed on double-negative lymphoid precursors after colonization of the thymus. Thus, immature thymocytes express the CD2 antigen before that of the CD3-TCR complex. We therefore investigated the responsiveness of these CD2+CD3- immature thymocytes and compared it with that of unseparated thymocytes, containing a majority of the CD2+CD3+ mature thymocytes, and that of the CD2-CD3- prothymocytes. Both immature and unseparated thymocytes were incorporating [3H]thymidine in response to the virus, provided that they were cultivated in the presence of submitogenic doses of phytohemagglutinin. In contrast, the prothymocytes did not proliferate. Downmodulation of the CD2 molecule by incubating unseparated and immature thymocytes with a single anti-CD2 monoclonal antibody inhibited the proliferative response to HTLV-I. These results clearly underline that the expression of the CD2 molecule is exclusively required in mediating the proliferative response to the synergistic effect of phytohemagglutinin and HTLV-I. Immature thymocytes treated with a pair of anti-CD2 monoclonal antibodies were shown to proliferate in response to HTLV-I, even in the absence of exogenous IL-2. We further verified that the proliferation of human thymocytes is consecutive to the expression of IL-2 receptors and the synthesis of IL-2. These observations provide evidence that the mitogenic stimulus delivered by HTLV-I is more efficient than that provided by other conventional mitogenic stimuli, which are unable to trigger the synthesis of endogenous IL-2. Collectively, these results show that the mitogenic activity of HTLV-I is able to trigger the proliferation of cells which are at an early stage of T-cell development. They might therefore represent target cells in which HTLV-I infection could favor the initiation of the multistep lymphoproliferative process leading to adult T-cell leukemia.
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PMID:Human T-cell leukemia virus type I-induced proliferation of human immature CD2+CD3- thymocytes. 810 12

The TCL1/MTCP1 oncogenes were identified on the basis of their involvement in T-cell prolymphocytic leukemia (T-PLL). TCL1 and MTCP1 proteins directly interact with AKT and modulate the AKT signal-transduction pathway, but the relevance of this mechanism in leukemogenesis remains unclear. We investigate the biologic functions of TCL1 in the T-cell lineage using various cell lines, and primary malignant and normal lymphocytes. In the Jurkat cell line, expression of TCL1 had no effect in unstimulated cells, whereas it abrogated activation-induced cell death (AICD). These cellular effects were concomitant with a major inhibition by TCL1 of PKCtheta and ERK pathways. Secondly, the TCL1-driven T-cell leukemia cell line SUP-T11 was shown to have impaired PKCtheta and ERK phosphorylation upon stimulation, which were restored by TCL1 inhibition using RNA interference. Finally, defects in these pathways were also observed in primary malignant (T-PLL) and transduced normal T lymphocytes expressing TCL1. Altogether, our data demonstrated that TCL1 inhibits AICD in T cells by blocking PKCtheta and ERK activation, upon cellular activation.
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PMID:The TCL1 oncoprotein inhibits activation-induced cell death by impairing PKCtheta and ERK pathways. 1784 28


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