Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myelogenous leukemia (CML) patients in chronic phase display compromised lymphokine-activated killer (LAK) cell induction, which is partly restored after therapy with interferon alpha. However, the relative resistance of the leukemic cells from these patients to autologous or allogeneic LAK lysis is not affected by this treatment. In an attempt to render CML cells more susceptible to lysis or cytostasis, they were precultured in serum-free medium with or without recombinant growth factors. In eight patients studied, interleukin-3 (IL-3) significantly enhanced the spontaneous short-term (6-day) proliferation of CML cells, with retention of ability to form colonies in methylcellulose. Culture in either medium alone or IL-3 led to a significant enrichment of CD14+ and CD33+ cells but to a reduction in CD34+ cells. In contrast, culture of the same cells in IL-2 (to generate autologous LAK activity) resulted in a loss of CD14+ and CD33+ as well as CD34+ cells but in a significant increase in CD3+ and CD56+ cells. Despite similarities in their phenotypes, IL-3 cultured cells but not those cultured in medium alone acquired susceptibility to lysis by the IL-2-cultured autologous LAK cells. These results may have significance for the design of novel combination immunotherapy in CML.
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PMID:Susceptibility of autologous target cells to lysis by lymphokine-activated effectors from interferon-alpha-treated chronic myelogenous leukaemia patients. 228 10

We generated a homogeneous population of cells with cytotoxic activity termed "adherent lymphokine-activated killer" (ALAK) cells from the peripheral blood of nine patients in the chronic phase of Ph1 positive chronic myelogenous leukemia (CML). The selective enrichment of CML ALAK cells depended on their propensity to adhere to plastic and proliferate when cultured in the presence of recombinant interleukin-2 (rIL-2) for 14 days. Culture of peripheral blood mononuclear cells under these conditions resulted in growth of a uniform population of cells with morphologic characteristics of large granular lymphocytes. The NKH1+/CD3- phenotype associated with IL-2-stimulated natural killer (NK) cells was present on 79% +/- 9% of cells. Absence of colony formation in conditions promoting the growth of CFU-GEMM indicated that the CML ALAK population was not contaminated with viable hematopoietic progenitors. Cytogenetic analysis of the CML ALAK population revealed 119/120 Ph1 negative metaphases and l/120 Ph1 positive metaphase in six patients. Southern blot analysis of CML ALAK failed to demonstrate a bcr gene rearrangement in seven patients known to have a bcr gene rearrangement in myeloid cells. Comparison of ALAK populations derived from peripheral blood of CML patients and normals revealed similar cytotoxicity against the NK-sensitive K562 cell line (104 +/- 36 LU v 88 +/- 19 LU; P = NS) and the NK-resistant Raji cell line (93 +/- 26 LU v 98 +/- 28 LU; P = NS). The proliferative capacity of CML ALAK cells (101 +/- 33 fold expansion) exceeds the growth potential of the normal ALAK cells (22.3 +/- 3 fold expansion; P = .02). Direct comparison of equal numbers of CML ALAK cells and a CML LAK cell population produced by incubation of peripheral blood mononuclear cells in rIL-2 for 14 days without adherence revealed that the CML LAK population had significantly lower lytic activity against K562 and Raji cell lines. We are able to expand CML peripheral blood mononuclear cells to provide a population of ALAK cells with potent cytotoxic activity. The CML ALAK population is relatively homogeneous, not contaminated with viable stem cells, not derived from a malignant lineage, and more cytotoxic than equal numbers of CML LAK cells. Further studies are underway to determine if this ALAK population may be effective in autologous killing of chronic myelogenous leukemia stem cells.
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PMID:Adherent lymphokine-activated killer cells in chronic myelogenous leukemia: a benign cell population with potent cytotoxic activity. 247 5

Supernatants were prepared from short-duration explant cultures of term human placentas obtained after cesarean delivery. These supernatants inhibited murine and human mixed lymphocyte reactions, as well as CTL generation. The effects were reversed by an excess of IL-2-containing medium. Similarly, the material inhibited human natural killer cytotoxicity against K 562 targets. The material was subjected to gel-filtration chromatography on an ACA 44 or Bio-Gel A15m column. The apparent MW of the MLR-CML material was about 60-70 kDa, whereas the NK inhibiting activity was eluted in high-MW components (greater than 200 kDa) as well as in the 50-kDa range. The relevance of this material in local immunoregulation during human pregnancy is discussed.
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PMID:Immunoactive products of human placenta. I. An immunoregulatory factor obtained from explant cultures of human placenta inhibits CTL generation and cytotoxic effector activity. 252 22

Even though they possess normal to increased numbers of circulating natural killer (NK) cells, patients with chronic myelogenous leukemia (CML) have a functional NK-cell deficiency which is restorable in vitro in the presence of recombinant IL-2. We therefore measured the level of IL-2 production by both T-helper and NK cells from CML patients as compared to normal controls using PHA-stimulated peripheral blood mononuclear cells (PBMs) as well as FACS-sorted CD4+ (OKT4+) lymphoid cells and FACS-sorted CD16+ (B73.1+) lymphoid cells. Peripheral blood mononuclear cells from CML patients demonstrated markedly defective IL-2 production as compared to normal controls (4.0 +/- 1.6 and 5.9 +/- 1.4 units/ml after 24 hr of 5 and 10 micrograms/ml PHA stimulation as compared with 40.7 +/- 10.3 and 69.3 +/- 15.1 units/ml for normal subjects). In addition to the decreased relative percentage of CD4+ (OKT4+) lymphoid cells in CML patients, FACS-sorted CD4+ (OKT4+) cells also demonstrated a significant defect in IL-2 production, (10.8 +/- 3.6 units/ml as compared to 39.0 +/- 5.8 units/ml after 24 hr stimulation with 10 micrograms/ml PHA). FACS-sorted CD16+ (B73.1+) lymphoid cells from CML patients also demonstrated significantly decreased IL-2 production after 24 hr incubation with increasing concentrations of PHA or with the NK-sensitive target K562 as compared to normal controls. Defective IL-2 production by PBMs, CD4+ (OKT4+), and CD16+ (B73.1+) cells from CML patients was also evident after 48 hr of PHA stimulation. Although the percentages of both T4+2H4+ and T4+4B4+ subsets are significantly decreased in CML patients, CML patients have normal ratios of T4+4B4+/T4+2H4+ subsets as compared to normal controls. These and previous results support the hypothesis that decreased IL-2 production by both T-helper and NK cells from CML patients may be mechanistically related to the observed NK-cell immunodeficiency in CML patients.
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PMID:Natural killer cell immunodeficiency in patients with chronic myelogenous leukemia. III. Defective interleukin-2 production by T-helper and natural killer cells. 252 12

Regulatory effects on myelopoiesis and myelogenous leukaemia cell proliferation mediated by a human T cell clone (TCC) carrying a gamma/delta receptor have been studied. MHC-unrestricted cytotoxicity could be induced in this clone by culture with IL-2 but not IL-4. Increasing concentrations of IL-2 resulted in increased lysis of natural killer (NK)-susceptible target cells but lysis of NK-resistant targets could not be induced. Moreover, cytotoxicity on fresh chronic myeloid leukaemia cells was not measurable even after culture with 1000 U/ml IL-2. However, NK-resistant targets could be lysed when anti-receptor antibodies (OKT3 or TCR-delta 1) were added to the assay. Clone 290-2 cells secreted lymphokines potentially inhibitory for myelopoiesis (TNF-alpha, IFN-gamma), and their supernatants could inhibit optimally stimulated granulocyte/macrophage colony formation by normal bone marrow. Moreover, 290-2 cells prevented the consistently observed IL-3-stimulated enhancement of proliferation of CML cells, although even IL-3-pretreated leukaemic cells were still resistant to lysis by this clone. Thus, cells of this type, even when not directly cytolytic, could have a role in the regulation of myeloid cell growth.
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PMID:Regulation of normal myelopoiesis and chronic myelogenous leukaemia cell proliferation through a non-cytotoxic mechanism by a gamma/delta T cell clone. 253 Jan 64

In vivo administration of an anti-interleukin-2 (anti-IL-2) receptor monoclonal antibody is a potential new therapy for prevention of allograft rejection of a freshly transplanted organ. Such an approach is more selective than targeting all T cells, or even the CD4 or CD8 major subsets, because only the very recently activated cells should be affected. A clinical trial of anti-Tac monoclonal antibody is in progress in which 20 mg of the immunoglobulin G 2a (lgG2a) antibody is administered intravenously daily for 10 days after cadaveric renal transplantation. Combinations with and without azathioprine, and with varying doses of cyclosporine with prednisone, are being evaluated in a randomized trial. Results to date show a significant immunosuppressive effect of anti-Tac, as measured by a reduced incidence and later onset of acute rejection episodes compared with cyclosporine plus prednisone or cyclosporine plus azathioprine plus prednisone. Removal or cytodestruction of IL-2-receptor positive cells from the peripheral blood does not occur to any major degree, even though serum levels of the antibody are always detectable. In addition, functional studies of MLR, CML, and suppressor cell generation 4 days after cessation of anti-Tac administration show no significant difference between treated and control groups The effect of anti-Tac seems, therefore, to be limited to inhibition of IL-2-mediated T-cell growth during the period of administration, with recovery after a few days' lag period.
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PMID:Prophylactic use of monoclonal anti-IL-2 receptor antibody in cadaveric renal transplantation. 268 58

Experiments were designed to evaluate the effect of recombinant IL-2 on growth of hemopoietic precursors from different sources (normal cord blood and bone marrow, and PB from CGL patients). For this purpose, combined cell sorting techniques and multipotent colony forming cell assays were used. A monoclonal antibody BI-3C5, which recognizes an antigen present on early lympho-myeloid cells as well as on all colony forming cells (CFU-GEMM assay), was used to enrich the studied populations. Double colour immunofluorescence techniques were performed to analyse the expression of Tac antigen on early progenitors. The results showed that rIL-2 had a stimulatory effect on growth of enriched progenitors from the three sources and surprisingly that addition of anti-Tac did not abolish this effect. On the contrary, anti-Tac enhanced even more growth of these sorted BI-3C5 precursors, suggesting a ligand action of the antibody. More interestingly, a low percentage of cord cells (1 in 1000) expressed both BI-3C5 and Tac antigens. The vast majority of cells did not concomitantly express both markers. The double labelled cells had a lymphoid-like morphology, high nucleus/cytoplasmic ratio and 2-3 nucleoli. The results will be discussed focusing on early and late "stem" cell growth.
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PMID:Recombinant interleukin 2 and anti-Tac influence the growth of enriched multipotent hemopoietic progenitors: proposed hypotheses for different responses in early and late progenitors. 312 93

We report a case of Ph1-negative, bcr-negative CML-BC, in which the primary leukemic cells displayed T-related antigens (CD7, CD4) in addition to HLA-DR and CD25 determinants. No B-lymphoid, myeloid and megakaryoblastic surface antigens were detected. In spite of this phenotype, DNA analysis revealed a germ-line configuration of the T-cell receptor beta chain gene region. Moreover, in-vitro culture studies demonstrated a proliferative response of the blast cell population to natural and recombinant myeloid-related factors, while no proliferative signal was observed in the presence of IL-2. The myeloid lineage was further demonstrated by the expression of myeloid-associated antigens on cultured blast cells, which still retained the CD7 antigen. Finally, cytogenetic analysis revealed a monosomy 7 which is usually associated with a stem cell leukemia. These results support the hypothesis that Ph1-negative, bcr-negative CML is characterized by the involvement of a multipotent stem cell capable of multilineage expression and indicate that differentiative and proliferative assays provide a further tool towards a more precise recognition of hematological disorders of uncertain origin.
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PMID:Multilineage cell involvement in Ph1-negative, bcr-negative chronic myeloid leukemia. 326 50

A great deal of information has emerged over the past decade regarding the gene structures and corresponding protein products of the cellular and transformation-associated forms of the ABL tyrosine kinase family. Many reports have also detailed the biological effects of these proteins (particularly the viral ABL forms) on a broad range of cell types. However, in spite of all these research efforts, the precise role of the ABL gene in normal and neoplastic growth remains to be determined. To elucidate the mechanism of action of normal and altered ABL proteins, it is imperative to identify their relevant cellular substrates and establish the role of the ABL target proteins in transformation and normal cellular growth. The availability of temperature-sensitive ABL proteins, coupled with the use of sensitive anti-phosphotyrosine antibodies, should be useful in this respect. Purification of enzymatically active, intact forms of the ABL proteins produced in insect cells by employing baculovirus expression vectors should permit direct comparison of the biochemical properties and tertiary structures of the various members of the ABL protein kinase family. Such studies will aid in understanding the nature of the alteration of ABL which results in the activation of its transforming potential. Furthermore, the availability of purified ABL proteins should permit examination of interactions of ABL with other growth-regulatory proteins, such as growth factor receptors. It has been shown that transformation-associated ABL proteins interact with the IL-3, IL-2 and GM-CSF growth-factor pathways. These and other components of the cellular signalling pathways are potential ABL targets. The elucidation of ABL function by a variety of approaches such as those described above will ultimately aid in the development of far-reaching therapeutic treatments for at least two forms of human leukaemia: Ph positive CML and Ph positive ALL.
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PMID:Role of the ABL oncogene tyrosine kinase activity in human leukaemia. 333 51

We have demonstrated that unstimulated highly-enriched NK cells have the capability to inhibit the growth of fresh clonogenic leukemic cells from AML, CML and preleukemic patients. The NK-cell population mediating antileukemic reactivity exhibited LGL morphology and NKH1 and CD16 phenotype. The inhibition of leukemic growth could be mediated by cell-to-cell contact or by soluble factor produced by NK cells. Antileukemia activity was only detectable when enriched population of LGL was utilized; NW-filtered lymphocyte population did not exhibit leukemia-inhibitory effect. However, such activity could be generated after culture of the latter effector cells with IL-2. The leukemia directed IL-2 activated effector cells were characterized as NK cells. The data reported here provide new insight into host factors which may control leukemia growth and indicate the possible future application of NK cells for therapy of leukemia.
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PMID:Inhibition of clonogenic growth of fresh leukemia cells by unstimulated and IL-2 stimulated NK cells of normal donors. 350 Oct 42


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