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)

Polycythaemia vera (PV) is a myeloproliferative disorder characterized by haematopoietic progenitor cells being hypersensitive to cytokines such as erythropoietin, interleukin-3, stem cell factor and insulin-like growth factor 1, which results in an increased production of mature blood cells. The pathogenetic cellular mechanism(s) behind this hypersensitivity to cytokines is unknown, but the number of cytokine receptors and the interaction between ligand and receptor are normal in PV. Interest has therefore focused on post-receptor mechanism(s). Haematopoietic cell phosphatase (HCP) is an intracellular tyrosine phosphatase that has been demonstrated to regulate proliferative signals negatively induced by the cytokines mentioned above. Moreover, motheaten mice that genetically lack HCP have an increased amount of erythroid progenitors that are hypersensitive to Epo, and patients with familial polycythaemia have been shown to exhibit a mutation of the Epo receptor gene that includes the docking site for HCP. We therefore studied mRNA expression of HCP in pure populations of CD34+ cells, granulocytes, platelets and lymphocytes from patients with PV, chronic myeloid leukaemia (CML) or essential thrombocythemia (ET), as well as healthy controls. Using a polymerase chain reaction analysis employing specific primers for HCP, we failed to detect any abnormalities of HCP expression in PV in any of the cell populations that were examined. Moreover, HCP mRNA expression was similar in ET and CML compared to controls. Finally, Western blot analysis revealed a normal HCP protein content in PV granulocytes and platelets. We therefore conclude that neither an impaired expression of the HCP gene nor a defect in HCP protein synthesis is present in PV, and does not seem to play a role in the aetiology of this disorder.
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PMID:No evidence for an altered mRNA expression or protein level of haematopoietic cell phosphatase in CD34+ bone marrow progenitor cells or mature peripheral blood cells in polycythaemia vera. 941 43

We evaluated the efficiency of adenovirus-mediated gene transfer into normal and malignant human hematopoietic cells. An E-1 and E-3 deleted, replication-defective recombinant Ad.RSV beta gal vector was used and the transduction efficiency was studied at a multiplicity of infection of 13 p.f.u. per cell. Approximately 40-50% of normal monocytes were transduced, whereas purified normal resting T cells and B cells were resistant to infection. We showed that 50-80% of primary chronic myeloid leukemia cells (CML, n = 12) were efficiently transduced in contrast to CML, successful transduction of resting primary chronic B lymphocytic leukemia cells required appropriate preactivation of targeted cells. A novel protocol for the efficient transduction of adenovirus into B-CLL cells was presented. We showed that anti-CD40 mAb or CD40 ligand acts in synergy with rhIL-4 to enable the transduction of approximately 50-75% of B-CLL cells (B-CLL, n = 6). Expression of beta-galactosidase in transduced CML cells and B-CLL cells was detected for at least 15 days after transduction. The present studies underline the utility of adenovirus vectors for the construction of cytokine gene-modified tumor vaccines for the treatment of hematopoietic malignancies such as CML and B-CLL.
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PMID:Efficient adenovirus-mediated gene transduction of normal and leukemic hematopoietic cells. 941 16

The effects of the administration of a 3-day course of 13-cis retinoic acid in combination with interferon a [RA/IFN] on the leukemia cells was measured in vivo in 43 patients with chronic myelogenous leukemia. The administration of RA/IFN was associated with a significant fall in the white blood cell count of patients with chronic-phase disease and with a fall in the percentage S-phase cells in CML patients regardless of the stage of their leukemia. In two thirds of the patients studied the administration of RA/IFN was also associated with an increase in marrow apoptosis. The cytokine combination also suppressed bcl-2 and myc expression in a minority of patients and such expression appears to be associated with response to a treatment regimen which includes RA/IFN. These studies are the first to directly assess the effects of the combination of RA/IFN on chronic myelogenous leukemia cells in vivo in patients. These effects, if seen in other malignant diseases, could account for the therapeutic benefit which has been associated with the administration of this combination of biological agents to patients with malignant disease.
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PMID:The effects of 13-cis retinoic acid and interferon-alpha in chronic myelogenous leukemia cells in vivo in patients. 944 43

Various clinical and laboratory observations suggest that the leukaemia cells in chronic myeloid leukaemia (CML) are potentially immunogenic. Whilst the ability of the leukaemia cells to elicit an anti-leukaemic immune response in the allogeneic setting is established, it remains unclear why such anti-leukaemic response does not occur in vivo in the autologous setting. We previously demonstrated the presence of leukaemia-reactive T cells in a patient with CML. However, we found that the T cells were normally anergic unless pre-incubated in vitro in high-dose recombinant interleukin-2. We speculated that the T cell anergy was the result of a lack of the appropriate immune costimulatory molecules on the leukaemia cell surface. In this study, we confirm the absence of immune costimulatory molecules, CD80 (B7-1) and CD86 (B7-2), on leukaemia cells and demonstrated that these costimulatory molecules on the leukaemia cells can be upregulated by a combination of GM-CSF and IL-4. There was an associated restoration of leukaemia cell immunogenicity to autologous T cells in mixed lymphocyte leukaemia reactions, suggesting a possible enhancement of anti-leukaemic reaction. More importantly, T cells primed with 'activated' leukaemia cells were able to recognise fresh cytokine-naive leukaemia cells. Furthermore, leukaemia cells expressing the dendritic cell marker, CD1a, were also generated. Our findings therefore suggest the opportunity in future to use these combination cytokines in vivo or these leukaemia cells which have been activated in vitro for leukaemia immunotherapy.
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PMID:Cytokine enhancement of immunogenicity in chronic myeloid leukaemia. 944 20

The hallmark of chronic myeloid leukemia (CML) is the chimeric tyrosine kinase oncogene bcr-abl. Since expression of bcr-abl mRNA frequently increases with disease progression and a duplication of the Philadelphia chromosome (harbouring the bcr-abl hybrid locus) represents the most frequent karyotypic abnormality in acute phase CML, we hypothesized that the level of BCR-ABL protein may affect the disease phenotype. Therefore, the biological effects of high and low levels of BCR-ABL expression were compared in growth factor-dependent and -independent myeloid and lymphoid cell lines. Our results demonstrated that low levels of BCR - ABL were sufficient to render these cell lines growth factor independent and tumorigenic, but higher levels were mandatory for additional protection against apoptotic stimuli. The provision of growth factor or an activated ras oncogene did not afford the same degree of protection as high levels of BCR-ABL and there were qualitative differences between the survival signals mediated by BCR-ABL and Bcl-2. These results have enabled us to establish a dose-dependent hierarchy of BCR-ABL induced biological effects, thus distinguishing the activation of pathways mediating protection from cytokine withdrawal from those protecting against other apoptotic stimuli.
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PMID:BCR-ABL activates pathways mediating cytokine independence and protection against apoptosis in murine hematopoietic cells in a dose-dependent manner. 946 59

Until recently, the only curative therapy for patients with chronic myelogenous leukemia (CML) who relapse after allogeneic bone marrow transplantation (BMT) has been second allogeneic BMT. Recently, donor mononuclear cells have been given to patients with relapsed CML to induce a potent graft-versus-leukemia reaction and re-establish complete remissions in the majority of patients without the need for a second transplant. The extraordinary success of donor mononuclear cell infusions shows that it is possible to manipulate and harness the graft-versus-leukemia (GVL) reaction for clinical benefit. The identity of the effector cells and target antigens is unclear, but intensive investigation is beginning to define the complex cytokine and cellular interactions that mediate GVL reactivity. Current clinical trials are investigating strategies that will retain and enhance the GVL effects while limiting toxicity from this therapy. Ultimately, the ability to harness the GVL potential of allogeneic donor cells without excessive toxicity from graft-versus-host disease will be a central challenge in BMT and cellular immunotherapy.
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PMID:Infusion of donor peripheral blood mononuclear cells to treat relapse after transplantation for chronic myelogenous leukemia. 952 29

The membrane-proximal cytoplasmic region of the granulocyte colony-stimulating factor receptor (G-CSFR) is known to be essential for the proliferation signal, with a more distal region being required for the differentiation signal. Such a separation of functional domains raises the possibility that mutations occurring at these regions may contribute to cell proliferation in the absence of differentiation, this being the most important characteristic in acute leukemia cells. Therefore, we analysed the structural abnormalities at the transmembrane and cytoplasmic region of G-CSFR in a significant number of patients with various myeloid malignancies. When we examined the genomic DNA of G-CSFR obtained from 41 patients with acute myelogenous leukemia (AML), 18 with chronic myelogenous leukemia (CML), 7 with myelodysplastic syndrome (MDS), 2 with chronic myelomonocytic leukemia and 1 with chronic neutrophilic leukemia, we found a polymorphism in 3 patients, but no significant pathogenic mutations in any patients. The screening for this polymorphism in 100 hematologically normal controls revealed that it may be useful as a linkage marker for population and family studies, because the heterozygosity index is at a high level (0.055). While there have been several reports discussing the leukemogenic potential of mutations in the cytokine/hematopoietin receptor superfamily, genetic alterations in the transmembrane and cytoplasmic region of G-CSFR do not seem to play a pathogenic role in leukemia.
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PMID:Analysis of the granulocyte colony-stimulating factor receptor gene structure using PCR-SSCP in myeloid leukemia and myelodysplastic syndrome. 954 19

All-trans retinoic acid (ATRA) and interferons (IFNs) are active anticancer agents. ATRA is capable of inducing complete remission in acute promyelocytic leukemia (APL) patients, whereas IFNalpha is successfully used in the treatment of the stable phase of chronic myeloid leukemia. ATRA and IFNs have shown synergistic interactions in various experimental conditions and represent a potentially useful therapeutic combination in the treatment of various types of leukemias and solid tumors. The molecular basis of these interactions are poorly understood and need to be elucidated. In this review, we summarize a series of recent observations concerning the molecular mechanisms underlying the cross-talk between the intracellular pathways activated by ATRA and IFNs in APL cells. In APL blasts, IFNs regulate the expression of retinoic acid receptors, and ATRA, in turn, modulates the levels and the state of activation of members of the Jak-STAT second messenger pathway. This demonstrates a two-way interaction between ATRA and IFNs, which leads to cross-modulation of genes normally under the control of the retinoid and the cytokine. These data may be relevant in the context of a rational use of the combination between ATRA and IFNs in the clinical management of myeloid leukemias.
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PMID:Cross-talk between retinoic acid and interferons: molecular mechanisms of interaction in acute promyelocytic leukemia cells. 971 9

Three-color flow cytometry immunophenotyping revealed significant increases of CD57+ and CD28- cells among both circulating CD4+ and CD8+ T lymphocytes of untreated hemato-oncological patients (n = 54) as compared to healthy donors (n = 55), with CD57 and CD28 expression on the patients' T cells being largely reciprocal. Marked expansion of CD57+ cells among circulating CD4+ T lymphocytes was frequently detected in patients with chronic leukemia of B cell origin (B-CLL, hairy cell leukemia) but not in patients with chronic myeloid leukemia, suggesting a causal relation with the tumor's major histocompatibility complex class II expression. Using immunomagnetic separation techniques, we further demonstrate that the patients' CD57+/CD28- T cells display a typical Th1-type cytokine secretion profile upon anti-CD3 stimulation, with a markedly higher secretion of the Th1-type cytokines IL-2, IFN-gamma, and TNF-alpha than their CD57-/CD28+ counterparts. Cytotoxic activity of circulating CD8+ T lymphocytes, measured ex vivo in an anti-CD3-redirected assay, was almost exclusively exerted by the CD57+/CD28- subset. Moreover, a marked cytotoxic activity was detected within CD4+CD57+ T cells from some B-CLL patients. Finally, the patients' CD57+/CD28- T cells displayed an increased tendency to apoptosis in culture. Collectively, our results indicate that the expanded CD57+/CD28- T cells in hemato-oncological patients represent differentiated effector cells, similar to their (quantitatively minor) counterpart in healthy donors. The reason for their expansion and their pathophysiologic significance, however, remains unclear.
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PMID:CD57+/CD28- T cells in untreated hemato-oncological patients are expanded and display a Th1-type cytokine secretion profile, ex vivo cytolytic activity and enhanced tendency to apoptosis. 976 2

We have developed culture conditions for the efficient expansion of cytotoxic effector cells from peripheral blood mononuclear cells (PBMNCs) by the timed addition of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and the monoclonal antibody (MoAb) OKT3. These cells, termed cytokine-induced killer (CIK) cells, are composed primarily of T cells, and the population of cells with the greatest cytotoxic activity is an otherwise rare population of CD3(+)CD56(+) cells that expand dramatically under these culture conditions. CIK cells were expanded from PBMNCs from 13 patients with chronic myeloid leukemia (CML). These cultures contained a variable number of T cells at the start of the culture (median 44%, range 1% to 64%), yet after 21 to 28 days of culture, virtually all of the cells were CD3(+) T cells (median 97%, range 90% to 99%). The CD3(+)CD56(+) subset of cells expanded significantly (median 25-fold, range 2.2- to 525-fold). CIK cells from all patients showed cytotoxicity against the tumor cell lines OCI-LY8 and K562. In four patients the expanded CIK cells suppressed colony growth of autologous CML blast cells and myeloid progenitor cells. Allogeneic CIK cells from normal donors also suppressed CML colony growth but did not inhibit growth of normal hematopoietic colonies. Twelve of the 13 cultures were exclusively composed of Philadelphia (Ph)-negative cells and one culture had 1 out of 20 Ph-positive metaphases after 4 weeks in culture. Intracellular cytokine production was assayed by fluorescence-activated cell sorter (FACS), and the expanded T-cell cultures produced IL-2, IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha), but not IL-4. Both the CD4(+) and CD8(+) subsets secreted this cytokine profile. To test the in vivo activity of the expanded CIK cells, CML was engrafted into severe combined immunodeficiency disease (SCID) mice using matrigel. After 4 weeks, 4 x 10(7) autologous CIK cells were injected intravenously by tail vein injection into groups of mice, and the animals were sacrificed after a total of 18 weeks. Bcr-abl was detected in the bone marrow or spleen of 5 out of 6 control mice and only 2 out of 13 mice who received the autologous CIK cells (P = .02). In an additional series of animals, the mice did not engraft with CML but instead developed large human Epstein-Barr virus-associated lymphomas by 12 weeks. The mice who received autologous CIK cells at 4 weeks had either no tumor (5) or small tumors (5), whereas all 10 mice that received CIK cells at week 8 developed lymphomas; however, these were not as large as in the 10 control mice who did not receive CIK cells (P = . 03). This study shows that CIK cells, which are Ph chromosome-negative, can be expanded from patients with CML and have potent in vitro and in vivo efficacy against autologous tumor cells.
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PMID:Expansion of Philadelphia chromosome-negative CD3(+)CD56(+) cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice. 978 69


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