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

The production of interleukin-2 (IL-2) by phytohemagglutinin (PHA)-stimulated human leukemia T cell lines was significantly increased by 6 different cytokines. The most effective cytokines were interleukin-1 alpha (IL-1 alpha) and IL-1 beta; less effective were interferon-alpha (IFN-alpha), tumor necrosis factor-alpha (TNF-alpha), IFN-beta and TNF-beta. The combinations of two cytokines had synergistic or additive effects and increased IL-2 production to a greater extent than either cytokine alone. Other cytokines tested, such as IL-3, IL-4, IL-6, IL-7, IL-8 and IFN-gamma, had no effect on IL-2 production. However, a remarkable heterogeneity in sensitivity to the enhancing effects of the active cytokines was found among the IL-2-producing T cell lines studied. While IL-2 production in the most sensitive cell line, MOLT-16, was increased by all 6 active cytokines, other cell lines responded by increasing IL-2 production to stimulation with only some of the cytokines tested. The production of IL-2 in T cell line H9 was not enhanced by any of the cytokines used. These results show that several cytokines can increase IL-2 production by having a direct effect on the activated IL-2-producing T cells, but also that the outcome of the regulatory effects of individual cytokines depends considerably upon the individual IL-2-producing T cell clone.
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PMID:Enhancement of interleukin-2 (IL-2) production by 6 different cytokines: heterogeneity among IL-2 producing T cell clones. 834 81

Previous experimental studies utilizing human recombinant interferon-alpha-2b (IFN alpha-2b) alone or with zidovudine (AZT) to treat established feline leukemia virus (FeLV) infection resulted in a significant reduction in circulating virus throughout a 49-day treatment period. However, the anti-FeLV effect of IFN alpha was limited by the production of IFN alpha-neutralizing antibodies detected 7 weeks after the start of treatment. AZT without IFN alpha had no effect on circulating virus load. To examine the hypothesis that combination chemoimmunotherapy might induce the clearance of FeLV infection, persistently infected cats were infused with activated lymphocytes, IFN alpha, and AZT 12 weeks after infection with FeLV. Recipient cats received weekly infusions of 1.46 x 10(8) lymphocytes activated in vitro with lectin/IL-2 comprised of 98% T cells and an even distribution of CD4+ and CD8+ lymphocytes. FeLV infection was cleared in 4 of 9 cats receiving combined therapy after four adoptive cell transfers. These cats remained negative for circulating virus during a 63-day treatment period (17 adoptive cell transfers) despite the production of anti-IFN alpha-neutralizing antibodies. Sequential development of virus-neutralizing and virus envelope antibody titers were detected in those cats which cleared retroviremia, an antiviral response that was absent in untreated control animals or nonresponders. Three of four responder cats remained negative for FeLV 95 days after treatment was discontinued. Treatment of cats with lymphocytes without chemotherapy failed to influence the course of FeLV infection. These results suggest that combined treatment using IFN alpha and adoptive lymphocyte transfer served to reconstitute antiviral humoral immunity, counteract immunosuppression, and induce the reversal of retroviremia.
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PMID:Reversal of feline leukemia virus infection by adoptive transfer of lectin/interleukin-2-activated lymphocytes, interferon-alpha, and zidovudine. 839 67

Interferon-alpha has been used as a differentiating agent in the treatment of patients with myelodysplastic syndrome with conflicting results and often significant toxicity. In order to maximize the differentiating effects of this agent and minimize the myelosuppressive effects, a prospective pilot study was initiated utilizing interferon alpha-2a (Roferon A, Roche Laboratories) in the treatment of complicated or poor prognosis myelodysplasia. The study regimen utilized 'mini-dose' interferon alpha-2a at 1 x 10(6) units subcutaneously three-times per week for 16 weeks followed by an 8 week observation period. Nine patients were enrolled between May 1990 and June 1991, of which seven are evaluable. Forty-three percent (3/7) had a partial or clinical response as defined by normalization of one or more of the hemoglobin concentration, white blood cell count, or platelet count, or a decrease in transfusion requirement by > or = 50%. Only one patient was removed from study for interferon-associated toxicity. Mini-dose interferon alpha-2a appears to be an effective regimen for some patients with myelodysplasia which can be administered with minimal toxicity. Further investigation with interferon-alpha for the treatment of myelodysplastic syndrome, at the dosage utilized in this study, is warranted.
Leukemia 1993 Feb
PMID:Mini-dose interferon alpha-2a in the treatment of myelodysplasia. 842 72

The CD25 molecule, which corresponds to the p55 alpha chain of the interleukin-2 receptor, is strongly expressed by neoplastic cells in hairy-cell leukemia and is released in large amounts in the soluble form which is detectable in serum. In order to assess the reliability of the soluble interleukin-2 receptor as a disease marker in the management of patients with hairy-cell leukemia, we investigated serum levels in 35 untreated patients and in 2 patients with the hairy-cell leukemia variant. In 21 of 35 patients soluble receptor levels were also monitored during and after recombinant interferon-alpha therapy. Clinical and hematological parameters were also assessed. Soluble interleukin-2 receptor levels were extremely high at the time of diagnosis in patients with typical hairy-cell leukemia [32,722 +/- 27,001 vs. 331 +/- 145 units/ml in controls (mean +/- SD)], but not in patients with the leukemia variant. A progressive decrease in soluble interleukin-2 receptor levels paralleled the clinical response to treatment, although normal values were never detected, even in patients who achieved an apparent complete remission. After recombinant interferon-alpha discontinuation, disease recurrence was accompanied by a progressive increase to pre-treatment soluble receptor levels. Overall, a close correlation was found between soluble interleukin-2 receptor values and total tumor burden (r = 0.84, P < 0.001). On the basis of these data, soluble interleukin-2 receptor should be regarded as a key marker in the management of patients with hairy-cell leukemia.
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PMID:Soluble interleukin-2 receptor in hairy-cell leukemia: a reliable marker of disease. 847 89

Potential anti-leukemia effects mediated by T cells or by natural killer (NK) cells were investigated in chronic myelogenous leukemia (CML) patients treated with interferon-alpha. Therapy-associated modulation of T cell and NK reactivity was monitored for one year from initiation in autologous mixed lymphocyte-tumor cell reactions and cytotoxicity directed against autologous CML cells, respectively. During the course of IFN-therapy, NK activity against autologous CML cells increased steadily, whereas T cell reactivity fluctuated randomly. Despite the high level of T cell reactivity to autologous tumor cells in short-term (6 days) culture, 1) they failed to respond to synthetic peptides corresponding to the bcr/abl fusion sequence of the patient, and 2) only one proliferative T cell clone (TCC) was isolated which specifically recognized HLA-DR-matched CML cells. This TCC appeared not to recognize synthetic peptides corresponding to the bcr/abl fusion sequence of the patient; the antigen to which it responds remains unknown. To assess potential immunogenicity of bcr/abl peptides, it was attempted to sensitize T cells from normal donors in vitro. Of 109 cell lines obtained from seven different donors, eleven showed peptide-dependent proliferation. Therefore, although these results show that it is possible to isolate apparently CML-specific T cells from patients, as well as to prime T cells against tumor-specific peptide in vitro, the frequency of such T cell-mediated reactivity appears low and its relevance to anti-leukemic effects questionable. On the other hand, the strong time-dependent enhancement of natural killing of autologous CML blasts during IFN-alpha treatment, a phenomenon not observed for T cell reactivity, suggests that natural immunity may be more important in controlling disease.
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PMID:Relative roles of natural killer- and T cell-mediated anti-leukemia effects in chronic myelogenous leukemia patients treated with interferon-alpha. 852 55

Cell line NKL was established from the the peripheral blood of a patient with CD3-CD16+CD56+ large granular lymphocyte (LGL) leukemia. The neoplastic LGL of this patient mediated natural killing and antibody-dependent cellular cytotoxicity (ADCC) and exhibited proliferative responses similar to normal CD16+CD56dim natural killer (NK) cells. The Morphology of NKL cells resembles that of normal activated NK cells. The karyotype of NKL is 47, XY, add (1) (q42), +6 del (6) (q15 q23), del (17) (p11). NKL cells express CD2, CD6, CD11a, CD26, CD27, CD29, CD38, CD43, CD58, CD81, CD94, CD95, class II MHC, and the C1.7.1 antigen, but do not express detectable levels of CD3, CD4, CD5, CD8, CD14, CD19, CD20, CD28, alpha/beta or gamma/delta T cell receptors on the cell surface. The density of the CD16, CD56, and CD57 antigens declined markedly on NKL cells during prolonged im vitro culture. Nevertheless, NKL cells can mediate ADCC as well as natural killing. NKL cells are strictly dependent on interleukin-2 (IL-2) for sustained growth and die if deprived of IL-2 for more than 7 days. NKL cells proliferate in response to concentrations of IL-2 as low as 1 pM, but an optimal proliferative response requires approximately 100 pM IL-2. NKL cells growing in the presence of IL-2 express abundant IL-2R alpha with little or no detectable IL-2 beta or gamma chain on the cell surface; NKL cells deprived of IL-2 express high levels of both IL-2R alpha and beta. IL-4, IL-7, and IL-12, unlike IL-2, do not maintain the viability of NKL cells. Furthermore, IL-1, IL-4, IL-6, IL-7, IL-12, tumor necrosis factor-alpha (TNF-alpha), interferon-alpha (IFN-alpha) and IFN-gamma do not support the growth of NKL cells. The NKL cell line may prove useful for studies of human NK cell biology.
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PMID:Characterization of a cell line, NKL, derived from an aggressive human natural killer cell leukemia. 859 69

The genes crucially determining the therapeutic response of chronic myelogenous leukaemia (CML) to interferon-alpha (IFN-alpha) are unknown. Recently, two independent IFN-alpha signalling pathways were identified: the classic pathway mediates induction of 2'-5' oligoadenylate synthetase (2-5 OAS), p68 kinase and IFN regulatory factor-2 (IRF-2), whereas the alternate pathway leads to activation of IFN regulatory factor-1 (IRF-1). We investigated whether deficient or imbalanced expression of components of these two pathways is associated with resistance of CML cells to antiproliferative action of IFN alpha/beta. Constitutive and IFN-induced transcript levels of IFN-dependent genes in mononuclear cells, granulocytes, monocytes, lymphocytes and CD34+ cells of chronic-phase CML and blast crisis patients were assessed by Northern blot techniques and were correlated with subsequent clinical responses to IFN therapy. Our results demonstrated that IFN-alpha or -beta treatment in vitro and in vivo leads to an enhanced expression of IRF-1, IRF-2. RNase L, p68 and 2-5 OAS which was independent of the degree of cellular differentiation and clonal evolution of CML. Neither the magnitude of induction of these genes nor the IRF-1/IRF-2 mRNA balance differed between chronic-phase CML patients responding or failing IFN-alpha therapy. These results indicate that failure of IFN-alpha treatment is not due to defects in mRNA induction of the above-mentioned candidate genes for the direct antiproliferative response to IFN type I.
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PMID:Induction of interferon regulatory factors 2'-5' oligoadenylate synthetase, P68 kinase and RNase L in chronic myelogenous leukaemia cells and its relationship to clinical responsiveness. 861 23

Abnormal adhesive interaction between bone marrow stroma and progenitors, one of the causes of unregulated proliferation in chronic myelocytic leukaemia (CML), may be caused by some alterations in adhesion molecules on CML progenitors. We investigated the expression of adhesion molecules (CD44, VLA-5, VLA-4, LFA-1, ICAM-1, L-selectin and c-kit) on bone marrow CD34++ cells from 16 CML patients by three-colour flow cytometry. The mean percentage of cells expressing L-selectin in the CD34++CD38+(or)++ fraction from untreated CML patients was significantly lower, and that in the CD34++CD38- fraction tended to be lower than that from normal controls. Among 11 CML patients treated with interferon-alpha (IFN-alpha), the mean percentage of the cells expressing L-selectin in the CD34++CD38- fraction from three patients with a low percentage of Ph1(+) cells in bone marrow was significantly higher than that from five patients with a high percentage of Ph1(+) cells. In addition, L-selectin expression rate was inversely correlated to the percentage of Ph1(+) cells. There was no significant difference between the untreated patients and normal controls with regard to the expression rates of the other adhesion molecules in each CD34++ fraction except LFA-1. These data suggest that decreased L-selectin expression in CML CD34++ cells reflects one of the features of malignant CML progenitors.
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PMID:Decreased L-selectin expression in CD34-positive cells from patients with chronic myelocytic leukaemia. 863 30

The type I interferons induce an anti-viral state and suppress cell growth. The p135tyk2 non-receptor tyrosine kinase appears to initiate, at least in part, the type I interferon signal transduction pathway, and thereby activates type I interferon-dependent gene expression. To determine if p135tyk2 can suppress growth and/or tumorigenesis, derivatives of the tyk2 gene were introduced into the tumorigenic cell line Daudi. Transfectants expressing a tyk2 construct missing the carboxy-terminal 22 amino acids cloned with a greatly reduced efficiency in soft agar and displayed a partial decrease in the ability to form tumors in athymic mice. In addition, transfectants producing a kinase deficient version of tyk2 show an increase in both growth rate and agar cloning efficiency, suggesting that the inactive kinase can act in a dominant-negative manner. Surprisingly, the carboxyl-terminal deleted protein lacks both auto-kinase activity, and activity towards a putative substrate, even though it induces a phenotype which is precisely the opposite of that produced by another kinase-deficient tyk2 mutant containing an altered ATP binding site. Thus, while these results add tyk2 to a growing list of interferon-alpha regulated proteins that might be able to suppress tumor formation, the biochemical basis of this activity remains unknown.
Leukemia 1996 Mar
PMID:A mutant form of p135tyk2, an interferon-alpha inducible tyrosine kinase, suppresses the transformed phenotype of Daudi cells. 864 73

One hundred and forty-three patients with p210 BCR-ABL-positive leukemia were studied for coexpression of p190 BCR-ABL mRNA. p190 mRNA was detected in 14 of 16 (88%) patients with chronic-phase chronic myeloid leukemia (CML) at diagnosis, in 10 of 10 (100%) CML patients in blast crisis, in 75 of 107 (70%) CML patients receiving interferon-alpha (IFN-alpha), and 10 of 10 (100%) patients with p210 BCR-ABL-positive acute lymphoblastic leukemia (ALL). Neither p210 nor p190 BCR-ABL transcripts were detected in normal healthy adults (n = 20). The numbers of p190 transcripts determined by competitive PCR in patients with CML were low compared with the numbers of p210 transcripts. The median numbers of p210 and p190 transcripts per unit volume of cDNA in positive samples were 1.0 x 10(5) (range, 15 to 1.4 x 10(6)) and 10 (range, 10 to 2.9 x 10(3)), respectively. The numbers of p190 and p210 transcripts were significantly correlated in individual samples (r = .65, P < .001). The median number of p210 BCR-ABL transcripts was significantly lower in samples negative for p190 BCR-ABL transcripts than in samples in which p190 BCR-ABL transcripts were identified (3.1 x 10(3)[n = 73] v 1.0 x 10(5)[n = 115]; P < .0001). The median ratio of p190 to p210 BCR-ABL mRNA was not significantly different between chronic phase CML (1.9 x 10(-4)) and CML in blast crisis (1.7 x 10(-4)). The median ratio in p210 ALL was also low (1.9 x 10(-3)) but significantly higher than that of CML. We conclude that pl90 BCR-ABL transcripts are frequently present at a low level in p210 BCR-ABL-positive leukemias. p190 mRNA may arise through alternative or missplicing and its presence is probably of no pathogenetic significance.
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PMID:p190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias. 865 35


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