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

To clarify whether regulatory cytokines inhibit hematopoiesis in patients with myelodysplastic syndromes (MDS), malignancies characterized by the formation of cytopenias despite the presence of cellular bone marrow, expression of TNF-alpha and IFN-gamma by bone marrow cells was investigated using specific reverse transcriptase-polymerase chain reaction assays. An enhanced expression of the mRNA for TNF-alpha was observed in most of the samples from MDS patients (11/14, 79%), whereas no enhancement was observed in bone marrow samples from AML (0/6), CML (0/2) or control cases (0/8). The expression of IFN-gamma was also enhanced in some of MDS cases (5/12, 42%) while AML (0/5), CML (0/2) and control cases (0/6) showed very low levels of IFN-gamma mRNA expression. Immunohistochemical examination confirmed the scattered presence of TNF-alpha or IFN-gamma producing cells in the bone marrow of MDS patients. The majority of these cells were CD68-positive macrophage lineage cells. These results suggested that disruption of hematopoiesis in MDS might be caused by enhanced production of inhibitory regulatory cytokines especially TNF-alpha and occasionally IFN-gamma by bone marrow macrophages.
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PMID:Overexpression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by bone marrow cells from patients with myelodysplastic syndromes. 944 19

We established two novel cell lines, designated as IMS-BC1 and IMS-BC2, from two patients with chronic myelogenous leukemia in blast crisis. The two cell lines were positive for CD13 and CD33 and negative for CD34 and HLA-DR by surface marker analysis. IMS-BC1 had four Philadelphia (Ph1) chromosomes and a breakpoint within the 3'-portion of M-bcr, and IMS-BC2 had five Ph1 chromosomes and two breakpoints within the 3'- and 5'-portions of M-bcr. Both cell lines' growth activities were moderately suppressed by IFN-alpha. The proliferation of IMS-BC2 was inhibited by IFN-gamma and apoptosis was induced within 72 h, while IMS-BC1 was resistant to IFN-gamma. Fibronectin inhibited the proliferation of the two cell lines at higher than 10 micrograms/ml, but only IMS-BC2 showed apoptosis. Transforming growth factor-beta inhibited the proliferation of IMS-BC2 resulting in apoptosis, while it inhibited that of IMS-BC1 moderately but failed to induce apoptosis. All-trans retinoic acid (ATRA) inhibited the proliferation of IMS-BC2 at very low concentration (10(-17) mol/l) and induced apoptosis at doses higher than 10(-9) mol/l within 72 h without terminal differentiation, while IMS-BC1 was completely resistant to ATRA. The two cell lines showed different responses to growth inhibitory cytokines and factors. These cell lines should prove useful in the analysis of mechanisms of apoptosis induced by growth inhibitory cytokines and factors.
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PMID:Establishment of novel cell lines derived from two patients with chronic myelogenous leukemia in blast crisis; IMS-BC1 and IMS-BC2 which exhibit markedly different sensitivity to apoptosis. 965 Apr 50

The contributions of cytokines to the development and progression of disease in a mouse model of retrovirus-induced immunodeficiency (MAIDS) are controversial. Some studies have indicated at etiologic role for type 2 cytokines, while others have emphasized the importance of type 1 cytokines. We have used mice deficient in expression of IL-4, IL-10, IL-4 and IL-10, IFN-gamma, or ICSBP-a transcriptional protein involved in IFN signaling-to examine their contributions to this disorder. Our results demonstrate that expression of type 2 cytokines is an epiphenomenon of infection and that IFN-gamma is a driving force in disease progression. In addition, exogenously administered IL-12 prevents many manifestations of disease while blocking retrovirus expression. Interruption of the IFN signaling pathways in ICSBP-/- mice blocks induction of MAIDS. Predictably, ICSBP-deficient mice exhibit impaired responses to challenge with several other viruses. This immunodeficiency is associated with impaired production of IFN-gamma and IL-12. Unexpectedly, however, the ICSBP-/- mice also develop a syndrome with many similarities to chronic myelogenous leukemia in humans. The chronic phase of this disease is followed by a fatal blast crisis characterized by clonal expansions of undifferentiated cells. ICSBP is thus an important determinant of hematopoietic growth and differentiation as well as a prominent signaling molecule for IFNs.
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PMID:Relationship of cytokines and cytokine signaling to immunodeficiency disorders in the mouse. 968 80

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

Long-term i.m. or s.c. injections of interferon-alpha, beta, and gamma(IFN) in patients with chronic myelogenous leukemia (CML) can cause severe, long-lasting cutaneous complications consistent with necrotizing vasculitis. The purpose of this study was to describe the cutaneous lesions and the course of illness in 7 well-documented patients with Philadelphia chromosome-positive (Ph+) CML treated with IFN. We reviewed 7 patients diagnosed with Ph+ CML at M.D. Anderson Cancer Center between 1983 and 1994 who experienced cutaneous lesions at the injection site after treatment with i.m. or s.c. IFN (3 patients treated with IFN-alpha, 3 with combined IFN-alpha and IFN-gamma, and 1 with IFN-beta). According to pathology reports available for 3 patients, the cutaneous lesions seem to be consistent with necrotizing vasculitis. The skin reactions occurred independent of the IFN type, administration modality (i.m. or s.c.), duration of previously received IFN therapy (3-108 months), stage of disease, and cytogenetic response to IFN treatment. Of 7 patients, 4 developed low-grade fever during the occurrence of skin reactions, but all cultures taken from the abscesslike lesions were negative for bacterial or fungal infection. These lesions either did not resolve and required surgical debridement (5 patients) or resolved slowly with conservative management that included discontinuation of IFN at the specific, involved site. Independent of the IFN type or i.m. or s.c. injections, IFN can cause painful and long-lasting cutaneous lesions that frequently require surgical intervention. Whether this is a result of the high concentration of IFN at the injection site, the diluent, or an immunologic reaction remains unclear.
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PMID:Local cutaneous necrotizing lesions associated with interferon injections. 980 17

To study the oncogenic role of the p210(bcr-abl) fusion protein in chronic myelogenous leukemia cells, we generated a mouse cell line that was stably transfected with and overexpressed the human p210(bcr-abl) fusion protein. We then looked for phosphorylation activation of the Janus-activated kinase (JAK) family of tyrosine-specific protein kinases by the p210(bcr-abl) fusion protein. We found that JAK1, which has been shown by others to be associated with the IFN-alpha and -gamma plasma membrane receptors, was phosphorylated to a much greater degree in cells containing the p210(bcr-abl) fusion protein than was the case in the original, untransfected cell line. In contrast, no phosphorylation of the JAK2 kinase, which is associated with the IFN-gamma but not IFN-alpha receptor, was observed either with or without p210(bcr-abl) protein. A substrate of JAK1, STAT1 (signal transducers and activators of transcription 1), was found to be phosphorylated in cells containing overexpressed p210(bcr-abl) fusion protein. These results indicate that the presence of the p210(bcr-abl) protein kinase within a cell is associated with phosphorylation of the JAK1 kinase and its substrate STAT1.
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PMID:Potential role of bcr-abl in the activation of JAK1 kinase. 981 65

In order to elucidate the possibility of costimulatory molecules-mediated immuno or immuno-gene therapy for human hematological malignancies, we analyzed 30 hematopoietic cell lines and cells obtained from 48 patients with hematological malignancies for the expression of costimulatory molecules such as CD80 and CD86. The 30 hematopoietic cell lines were composed of 4 cell lines derived from the patients with T-cell acute lymphoblastic leukemia (T-ALL), 3 from Philadelphia chromosome positive ALL (Ph1+ALL), 8 from acute myeloblastic leukemia (AML), 3 from acute promyelocytic leukemia (APL), 8 from chronic myeloid leukemia at blast crisis (CML-BC), 3 from Burkitt's lymphoma and one from follicular cell lymphoma. The expression of CD80 or CD86 was frequent on cell lines derived from the patients with CML-BC or Burkitt's lymphoma, while it was rare on cell lines from T-ALL. Subsequently we analyzed the cells obtained from 48 patients with hematological malignancies, which consisted of 6 samples from patients with ALL, 30 from AML, 2 from CML-BC, 3 from B-cell lymphoma and one from each acute mixed leukemia (AMixL), adult T cell leukemia (ATL), T-cell large granular lymphocytic leukemia (T-LGL leukemia), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS)-RAEB in T, multiple myeloma (MM) or T-cell lymphoma. Among all the 48 cases, all cases except one case with CLL and two with B cell lymphoma were demonstrated to be negative for CD80 on the neoplastic cells. CD86 and HLA-DR were shown to be expressed in 50% and 88% of total 48 cases respectively. In 30 AML samples, CD86 was positive in 15 cases (50%), which was sharply in contrast with the finding that CD80 was not detected in any AML samples. HLA-DR was expressed in 25 AML samples (83%). We also treated seven human hematopoietic cell lines with IFN-gamma, IL-12 or IL-15 and observed whether these cytokines could induce or enhance the expression of CD40, CD54, CD58 and HLA-DR as well as CD80 and CD86. The present study demonstrated that the expression of CD86 could be upregulated not only by IFN-gamma, but also by IL-12 or IL-15 in some cell lines. These findings suggested the possibility that the absence of CD80 on neoplastic cells may be associated with the lack of efficient anti-tumor immunity in most patients with hematological malignancies and that the immuno or immuno-gene therapy manipulating the expression of costimulatory molecules such as CD80 may be a useful treatment modality for hematological malignancies.
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PMID:Expression patterns of costimulatory molecules on cells derived from human hematological malignancies. 989 58

The pathogenic mechanisms of immunosuppression leading to susceptibility of Mycobacterium tuberculosis (MT) infection in chronic myelocytic leukemia (CML) are not clear. To address this issue, we measured the proliferative response, variation of T cell subpopulations (CD4+, CD8+, TCR-V delta 2 and TCR-V beta 8 T cells) and the cytokine profile (IL-1 beta, IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma) after MT stimulation of peripheral blood mononuclear cells (PBMC) in a patient with concomitant CML and active pulmonary tuberculosis. The results were compared to four patients with active pulmonary tuberculosis and no other coexistent diseases. The immunologic response to phytohemagglutinin (PHA) was also evaluated. In contrast to controls, the CML PBMC failed to proliferate in response to MT antigens. Mycobacterium-reactive CD4+, V delta 2 and V beta 8 T cells did not expand after MT stimulation of the CML PBMC. In MT antigens-stimulated cultures from the CML patient, IL-2 was not produced and mild reduction of IL-1 beta and INF-gamma were observed. In contrast, IL-10 was markedly elevated in these cultures. Similarly, PHA-stimulated PBMC from the CML patient showed no expansion of CD4+ and CD8+. T cells. In these cell cultures, INF-gamma concentration in supernatants was decreased and IL-10 was significantly elevated. This study suggests that patients with CML may present a profound immunosuppression of essential cellular and molecular immune effectors, a scenario which might contribute to the development of active tuberculosis. These findings further support the need of establishing immunotherapeutic modalities with potential value for myeloproliferative disorders.
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PMID:Abnormal immunological response to Mycobacterium tuberculosis antigens in a patient with chronic myelocytic leukemia and active tuberculosis. 1002 42

Interferons (IFNs) have been implicated in the pathogenesis of sarcoidosis. In particular, IFN-gamma has been linked to pulmonary macrophage activation, a characteristic feature of sarcoidosis. IFN-alpha is now being administered therapeutically in a variety of conditions. To date, IFN-alpha has not been implicated in the pathogenesis of sarcoidosis. We report the case of a 50-year-old woman who developed sarcoidosis while being treated with IFN-alpha for chronic myelogenous leukemia. Her disease activity correlated with the dosage of IFN-alpha. We speculate that the immunomodulatory effects of IFN-alpha triggered clinical manifestations of sarcoidosis in this patient.
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PMID:Interferon-alpha therapy associated with the development of sarcoidosis. 1063 Dec 39

Three different types of anti-T cell antibody were used in patients undergoing haematopoietic stem cell transplantation (HSCT) with an HLA-A, -B and -DR compatible unrelated donor: ATG-Fresenius (ATG-F) (n = 26), Thymoglobuline (TMG) (n = 61) and OKT-3 (n = 45). The groups were comparable regarding diagnosis, stage, age, conditioning and GVHD prophylaxis, Adverse events were less frequent after ATG-F treatment. Levels of IL-2, IL-6, IFN-gamma, TNF-alpha and GM-CSF were increased after OKT-3 infusion. In multivariate analysis OKT-3 treatment (P = 0.01), G-CSF treatment (P = 0.02) and a cell dose >/=2.7 x 108/kg (P = 0.03) gave a faster engraftment. Acute GVHD grades II-IV occurred in 25% of the ATG-F patients, 12% of the TMG-patients and 43% (P < 0.001 vs TMG) of the OKT-3 patients. OKT-3 was associated with acute GVHD in multivariate analysis. TRM was 26% using TMG as compared to 43% in the OKT-3 group (P = 0.03). Patient survival at 4 years was 63%, 50% and 45% in the ATG-F, TMG and OKT-3-treated patients, respectively (NS). Relapses were 8%, 49% and 34%, respectively (ATG-F vs TMG, P = 0.03). Relapse-free survivals were 61%, 40% and 37% (NS). Among CML patients the probability of relapse was 61% in TMG-treated patients, while no patients relapsed in the other two groups. To conclude, the type of anti-T cell antibody affects GVHD and relapse after HSCT using unrelated donors.
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PMID:Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies during conditioning for unrelated haematopoietic stem cell transplantation. 1051 91


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