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)

A human leukemia cell line, SUP-T13, can gain and lose TCR/CD3 expression at rates incompatible with spontaneous mutation. In this study, we determined (i) the generality of this phenomenon among other T cell lines, (ii) the specificity of this phenomenon to the TCR/CD3 complex, and (iii) the molecular mechanism of TCR/CD3 loss in the SUP-T13 cell line at a biochemical level. We show that two other T cell lines can undergo gain and loss of TCR/CD3 expression at similar rates. However, class I MHC molecules do not switch expression on and off, demonstrating that such switching is not an artifact of the analysis. To determine the mechanism for loss of surface TCR/CD3 expression, pulse-chase labeling and immunoprecipitation were performed on SUP-T13 TCR/CD3 negative cells. These analyses revealed that TCR alpha proteins are produced, but do not covalently associate with TCR beta-CD3 proteins in the negative cells. Thus, these variants represent a novel level of posttranslational regulation of TCR/CD3 expression, namely, the disulfide linkage of alpha and beta TCR chains.
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PMID:A reversible defect in alpha-beta T cell receptor assembly. 863 87

ETV6 (TEL) is rearranged in various types of hematologic malignancies. The B-cell precursor acute lymphoblastic leukemia (ALL) cell line SUP-B2 has a t(6;12)(q23;p13) involving ETV6 at 12p13 and a submicroscopic deletion of the other ETV6 allele. The reciprocal translocation results in the fusion of ETV6 to a previously unknown gene at 6q23, which we named STL (six-twelve leukemia gene). Both reciprocal fusion transcripts can be detected: On the der(6) chromosome, the ETV6/STL mRNA shows an apparently out of frame fusion of ETV6 at nucleotide 187 to STL, which would result in the addition of 14 amino acids to the first 54 amino acids of ETV6. On the der(12) chromosome three different variants of the STL/ETV6 fusion mRNA could be detected; variable size segments were inserted at the breakpoint between STL and ETV6 exon 3. One of these variants could give rise to a protein in which the first 54 amino acids of ETV6 are replaced by 12 amino acids from one of the STL short open reading frames. Sequence analysis of a 1.4 kb STL cDNA clone from a skeletal muscle library revealed no long open reading frames. This cell line will be very useful in studying the different mechanisms by which alterations of ETV6 contribute to leukemogenesis and in testing the hypothesis that ETV6 might act as a tumor suppressor gene.
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PMID:A t(6;12)(q23;p13) results in the fusion of ETV6 to a novel gene, STL, in a B-cell ALL cell line. 908 65

Recent studies have shown that hepatocyte growth factor (HGF) is a regulatory protein for the proliferation and differentiation of hematopoietic progenitors. The proto-oncogene c-met encodes a tyrosine kinase receptor that binds HGF. To obtain information about their possible involvement in the pathogenesis of hematopoietic tumors, we have examined the expression of HGF and c-met in a large panel of leukemia-lymphoma cell lines encompassing all major hematopoietic cell lineages. HGF and c-met mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blotting. The panel of 92 cell lines analyzed comprised seven B-cell precursor, ten B-cell, six plasma cell, 13 T-cell, four natural killer (NK) cell, 16 myelocytic, 12 monocytic, 13 erythroid-megakaryocytic and 11 Hodgkin-anaplastic large cell lymphoma (ALCL) lines. In total 64 (70%) were RT-PCR-positive for HGF and 43 (47%) for c-met. The highest percentages of expression were found for HGF in the plasma cell (100%), NK (100%) and myeloid (75-92%) cell line categories, whereas c-met was found predominantly in plasma cell (100%) and Hodgkin-ALCL (91%) cell lines. The concomitant expression of HGF and c-met in plasma cell lines (100%) and Hodgkin-ALCL (73%) cell lines should be noted. The high HGF expression in myelocytic-monocytic cell lines (75 and 92%) contrasts with the low c-met expression (18 and 8%) in these cell lineages. In 50 cell lines, mRNA expression of these two genes was also examined at the Northern blot level: 12/50 (24%) and 4/48 (8%) were positive for HGF and c-met mRNA expression, respectively. Of note, three of the four c-met + lines belonged to the category Hodgkin-ALCL; the Hodgkin cell line SUP-HD-1 showed both HGF and c-met mRNA bands suggesting the possibility of an autocrine loop. In conclusion, we detected HGF expression in various types of leukemia-lymphoma cell lines, particularly in plasma cell and myeloid malignancies; c-met expression was found in plasma cell and Hodgkin-ALCL cell lines. Further detailed analysis of the role of this ligand-receptor pair in the pathogenesis of hematopoietic neoplasms is indicated; to this end the HGF + and c-met + cell lines described here represent exquisite model systems.
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PMID:Expression of hepatocyte growth factor and its receptor c-met in human leukemia-lymphoma cell lines. 971 11

We established a monoclonal antibody, 3G12 (IgG1), with antiproliferative effects on a human T-cell leukaemia cell line, SUP-T13. Among haematolymphoid cell lines, 3G12 reacted with most T-cell lines, Epstein-Barr transformed B-cell lines, some myelomonocytic cell lines and, most strongly with an anaplastic large cell lymphoma (ALCL) cell line, Karpas 299. The cell panel reactive with 3G12 was similar, but not identical, to that of the anti-CD30 antibody Ber-H2. 3G12 induced Fas-independent apoptosis in SUP-T13 and it also induced growth-inhibition in a limited number of other cell lines, but not Karpas 299. Immunohistochemical studies on paraffin-embedded tissue specimens demonstrated that 3G12 reacted with most CD30-positive ALCL cases and some T-cell lymphomas and some Hodgkin's lymphomas, but not with B-cell lymphomas or non-haematogeneic tumours. The immunoprecipitation study with 3G12 demonstrated a major band of 200 kD and a minor band of 100 kD, which were different from CD30. Thus 3G12 defines a novel antigen that shares a similarity to CD30 in terms of distribution among haemopoietic cells. The data suggest that the 3G12-defined antigen, designated Hal-1, is important as a marker for ALCL and may play a role in its pathogenesis.
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PMID:A monoclonal antibody, 3G12, reacts with a novel surface molecule, Hal-1, with high expression in CD30-positive anaplastic large cell lymphomas. 1044 63

We designed a novel multiplex in-cell reverse transcription-polymerase chain reaction method for the simultaneous detection and differentiation of p190 and p210 BCR-ABL mRNAs within single cells from the human chronic myeloid leukemia and Philadelphia positive acute lymphoblastic leukemia. Human K562 chronic myeloid leukemia and SUP B-15 Ph+ acute lymphoblastic leukemia cell lines were used as positive controls for p210 and p190 BCR-ABL mRNAs, respectively. HL60 cell line was used as a negative control. After the leukemia cells were fixed and permeabilized, without extracting nucleic acids, the mRNAs were reverse transcribed to cDNAs, and the cDNAs were amplified by multiplex polymerase chain reaction with fluorescent primers specific for p190 and p210 BCR-ABL mRNAs. After transfer onto glass slides by cytospin, the amplified cells were detected by fluorescence microscopy. Fluorescence microscopy after propidium iodide or 4',6-diamidino-2-phenylindone counterstaining showed that the positive K562 cells exhibited a yellow-green fluorescent cytoplasm around a red nucleus, and that the positive SUP B-15 cells exhibited an orange cytoplasm around a blue nucleus. Only the red or blue nucleus was visible in respective negative HL60 cells. The specificity of amplification was confirmed by the absence of a signal when control experiments were performed either with RNase digestion of mRNA or without reverse transcriptase/Taq polymerase. We conclude that the multiplex in-cell reverse transcription-polymerase chain reaction method is capable of simultaneously detecting and differentiating the p210 and p190 BCR-ABL mRNAs of chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia cells, and that it may be useful in quantitatively monitoring the minimal residual disease during therapy.
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PMID:Multiplex in-cell reverse transcription-polymerase chain reaction for the simultaneous detection of p210 and p190 BCR-ABL mRNAs in chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia cell lines. 1109 54

Notch genes encode a family of transmembrane proteins that are involved in many cellular processes, such as differentiation, proliferation, and apoptosis. It is well established that all four Notch genes can act as oncogenes; however, the mechanism by which Notch proteins transform cells remains unknown. Previously, we reported that both nuclear localization and transcriptional activation are required for neoplastic transformation of RKE cells. Furthermore, we identified cyclin D1 as a direct transcriptional target of constitutively active Notch molecules. In an effort to understand the mechanism by which Notch functions in the nucleus, we sought to determine if Notch formed stable complexes using size exclusion chromatography. Herein, we report that the Notch intracellular domain (N(ic)) forms distinct high-molecular-weight complexes in the nuclei of transformed RKE cells. The largest complex is approximately 1.5 MDa and contains both endogenous CSL (for CBF1, Suppressor of Hairless, and Lag-1) and Mastermind-Like-1 (Maml). N(ic) molecules that do not have the high-affinity binding site for CSL (RAM) retain the ability to associate with CSL in a stable complex through interactions involving Maml. However, Maml does not directly bind to CSL. Furthermore, Maml can rescue Delta RAM transcriptional activity on a CSL-dependent promoter. These results indicate that deletion of the RAM domain does not equate to CSL-independent signaling. Moreover, in SUP-T1 cells, N(ic) exists exclusively in the largest N(ic)-containing complex. SUP-T1 cells are derived from a T-cell leukemia that harbors the t(7;9)(q34;q34.3) translocation and constitutively express N(ic). Taken together, our data indicate that complex formation is likely required for neoplastic transformation by Notch(ic).
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PMID:Characterization of a high-molecular-weight Notch complex in the nucleus of Notch(ic)-transformed RKE cells and in a human T-cell leukemia cell line. 1199 24

Clotrimazole is an antimycotic imidazole derivative that interferes with cellular Ca(2+) homeostasis. We investigated the effects of clotrimazole on acute lymphoblastic leukemia (ALL) cells. Treatment with 10 microM clotrimazole (a concentration achievable in vivo) reduced cell recovery from cultures of all nine ALL cell lines studied (B-lineage: OP-1, SUP-B15, RS4;11, NALM6, REH, and 380; T-lineage: MOLT4, CCRF-CEM, and CEM-C7). After 4 days of culture, median cell recovery was 10% (range, <1% to 37%) of cell recovery in parallel untreated cultures. Clotrimazole also inhibited recovery of primary ALL cells cultured on stromal feeder layers. After leukemic cells from 16 cases of ALL were cultured for 7 days with 10 microM clotrimazole, median cell recovery was <1% (range, <1% to 16%) of that in parallel untreated cultures. Clotrimazole was active against leukemic cells with genetic abnormalities associated with poor response to therapy and against multidrug-resistant cell lines. In contrast, mature T lymphocytes and bone marrow stromal cells were not affected. Clotrimazole induced depletion of intracellular Ca(2+) stores in ALL cells, which was followed by apoptosis, as shown by annexin V binding and DNA fragmentation. Thus, clotrimazole is cytotoxic to ALL cells at concentrations achievable in vivo.
Leukemia 2002 Jul
PMID:The antifungal antibiotic clotrimazole alters calcium homeostasis of leukemic lymphoblasts and induces apoptosis. 1209 59

A baculovirus-expressed chimeric recombinant IgG1 (rIgG1) antibody, with Cgamma1 and Ckappa human constant domains, was derived from the murine monoclonal antibody 13B8.2, which is specific for the CDR3-like loop of the CD4 molecule. The recombinant IgG1 antibody 13B8.2 was previously shown to inhibit HIV-1 replication and to abrogate the one-way mixed-lymphocyte reaction and block proliferation of CD3-stimulated peripheral blood CD4 lymphocytes from healthy donors. Before testing this recombinant anti-CD4 antibody in in vivo preclinical trials, in vitro mechanisms of action of rIgG1 13B8.2 were assessed using various CD4 T-cell lymphomas. The baculovirus-expressed rIgG1 13B8.2 antibody led to 14% to 40% proliferation inhibition of the lymphoblastic leukaemia-derived SUP-T1, the acute T lymphoma-derived CCRF-CEM and Jurkat, and the cutaneous T-Cell lymphoma-derived HUT-78 cell lines, but it did not affect the cell cycle nor induce cell apoptosis. rIgG1 antibody 13B8.2 bound the C1q fraction, leading to 9% to 17% complement-mediated lysis of the HUT-78, H9, Sup-T1, and the CCRF-CEM cell lines. No correlation was observed between cell sensitivity to rIgG1 13B8.2-triggered complement-dependent lysis and CD35-, CD46-, CD55-, and CD59-surface expression on T lymphoma cells. Using fluorescence-activated cell sorter analysis, the antibody was shown to bind to FcgammaRI/CD64-transfected IIA1.6, FcgammaRII/CD32-transfected CDw32L, and FcgammaRIII/CD16-transfected Jurkat CD16 cell lines. In correlation with these findings, rIgG1 13B8.2 induced 11% to 31% antibody-dependent cell-mediated cytotoxicity of the CCRF-CEM, SUP-T1, A2.01 CD4, and Jurkat cell lines. These convincing results on the activity of the recombinant chimeric anti-CD4 antibody 13B8.2 have led us to perform in vivo preclinical study in a murine xenograft model of CD4 lymphomas.
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PMID:In vitro antitumoral activity of baculovirus-expressed chimeric recombinant anti-CD4 antibody 13B8.2 on T-cell lymphomas. 1747 Nov 66

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

CEM, MOLT4 and SUP-B15 cells were transduced with lentivirus-mediated siRNA KIS gene. The mRNA expressions of KIS were successfully reduced in all cell lines. On the other hand, the mRNA expressions of p27(Kip1) in CEM, MOLT4 and SUP-B15 cells were not affected by the transduction with siRNA KIS gene. We showed that KIS protein directly interacted with p27(Kip1) protein, and reduction of KIS inhibited the S10 phosphorylation of p27(Kip1) in leukemia cells. On these cells transfected with siRNA KIS, the inhibition of S10 phosphorylation of p27(Kip1) was strongly suppressed cell proliferation in a time-dependent manner. Moreover, the inhibition of S10 phosphorylation of p27(Kip1) increased a significant population in G0/G1 fraction. These data demonstrated that the KIS activity was induced during G0/G1, and it promotes cell cycle progression by phosphorylation of S10 on p27(Kip1). We showed that KIS mRNA expression was increased in primary leukemia specimens (acute myelogenous leukemia (AML); 37, myelodysplastic syndrome (MDS); 72, acute lymphoblastic leukemia (ALL); 23), and the mean ratios of KIS to G3PDH in AML, MDS and ALL specimens were 3.62+/-0.68, 3.27+/-0.73 and 3.17+/-0.58, respectively. Moreover, we found that KIS protein was overexpressed in all 132 adults cases of various leukemias, including 37 AML (8 M1, 12 M2, 2 M3, 7 M4, 8 M5), 72 MDS (42 RAEB-I, 30 REAB-II) and 23 ALL (23 L2). This study demonstrates that the elevated levels of KIS protein in leukemia cells promote the cell cycle progression in leukemia cells.
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PMID:KIS induces proliferation and the cell cycle progression through the phosphorylation of p27Kip1 in leukemia cells. 1838 76


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