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)

The studies described here demonstrate that in vitro processing of cells before extraction of RNA has a major effect on the number and type of cytokine transcripts present within MDS and leukemia cells. Transcripts for GM-CSF, a cytokine whose production by leukemia cells is believed to play an important role in the pathogenesis of leukemia, was not detectable in 12/13 unprocessed AML specimens, in 12/12 MDS specimens, or in 7/7 CML specimens but once detected in many specimens after processing. These data strongly suggest that leukemia cell production of GMCSF rarely occurs in vivo.
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PMID:Cytokine production by in vitro processed and unprocessed haematopoietic cells. 1088 Feb 62

Interferon (IFN) is an effective treatment for chronic myeloid leukemia (CML) in chronic phases, and a number of in vitro antileukemic effects of IFN on CML cells have been reported. The transfer of cytokine genes into tumor cells is reportedly a valuable approach to improve the antitumor activity of cytokines in various models. We first investigated the possibility of transducing CML cells with the retroviral vectors LIalpha2SN and LIgammaSN, encoding the IFN-alpha2 and IFN-gamma genes, respectively, and with the bicistronic vector LIalpha2IrIgammaSN coexpressing the IFN-alpha2 and IFN-gamma genes. We then analyzed the effects of IFN-alpha2 and IFN-gamma produced alone or simultaneously on the proliferation of CML cells. We optimized the transduction efficiency by using the CML-derived K562 cell line. We then introduced IFN genes into CML CD34+ cells. Secretion of IFN-alpha and IFN-gamma was demonstrated in K562 and CML CD34+ cells transduced with the different vectors. The MHC class I antigens were overexpressed in both K562 and CML CD34+ transduced cells. Inhibition of the proliferation of LIalpha2IrIgammaSN-transduced CML cells was greater than with the LIalpha2SN and the LIgammaSN-transduced CML cells. We demonstrate an additive effect of IFN-alpha and IFN-gamma on the inhibition of K562 and CML CD34+ cell proliferation.
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PMID:Retroviral coexpression of IFN-alpha and IFN-gamma genes and inhibitory effects in chronic myeloid leukemia cells. 1088 14

Signal transducers and activators of transcription (STATs) are a family of transcription factors that were originally identified as mediators of cytokine-induced gene expression. We and others have recently shown that STAT5 also plays a major role in cellular transformation by the Bcr-Abl oncogene. Here we show that the antiapoptotic bcl-xL gene product and the cell cycle regulator cyclin D1 are targets of STAT5 in Bcr-Abl-transformed cells. In the CML cell line K562 and in BaF3 cells ectopically expressing Bcr-Abl, both the cyclin D1 and bcl-x promoters are highly active. The activity of these promoters can be strongly repressed by cotransfection of a dominant negative (DN) mutant of STAT5. Moreover, the cyclin D1 and bcl-x promoters contain STAT binding sites to which STAT5 constitutively binds in Bcr-Abl transformed cells. These results suggest that STAT5 contributes to transformation by Bcr-Abl by induction of cyclin D1 and bcl-xL expression.
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PMID:STAT5-Dependent CyclinD1 and Bcl-xL expression in Bcr-Abl-transformed cells. 1096 54

It was previously shown that patients with chronic myeloid leukemia (CML) have a rare but consistently detectable population of quiescent (G0) leukemic (Philadelphia chromosome-positive and BCR-ABL-positive [BCR-ABL+]) CD34+ cells. In the study described here, most such cells expressed a primitive phenotype (CD38-, CD45RA-, CD71-, and HLA-DR(lo)) and cultures of these cells containing growth factors produced ultimately larger, but initially more slowly growing clones than do cultures of initially cycling CD34+ leukemic cells. Initially quiescent leukemic cells expressing BCR-ABL proliferated in single-cell cultures in the absence of added growth factors, thereby demonstrating their ability to spontaneously exit G0 and enter a continuously cycling state. Interestingly, on isolation, few of these quiescent BCR-ABL+ cells contained either interleukin-3 (IL-3) or granulocyte colony-stimulating factor (G-CSF) transcripts, whereas both were present in most cycling BCR-ABL+ CD34+ cells. However, after 4 days of culture in the absence of added growth factors and in association with their entry into the cell cycle (as indicated by up-regulation of Ki-67 and cdc25 transcripts), IL-3 transcripts became detectable. These findings show that entry of leukemic (BCR-ABL-expressing) progenitors into a quiescent (G0) state in vivo is highest among the most primitive leukemic cell populations, associated with a down-regulation of IL-3 and G-CSF gene expression, and spontaneously reversible in association with up-regulation of IL-3 expression. These results highlight the potential physiologic relevance of quiescent CML progenitors, even in treated patients, in whom these cells would be predicted to have a proliferative advantage over their quiescent normal counterparts when cytokine concentrations are low.
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PMID:Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. 1115 90

Coeliac disease (CD) is caused by a CD4 T helper cell type 1 (Th1) response in the small intestinal mucosa to dietary gluten. As the major Th1 inducing cytokine, interleukin 12, is undetectable in CD gut mucosa, the mechanism by which Th1 effector cells are generated remains unknown. Interferon (IFN) alpha, a cytokine capable of promoting IFN-gamma synthesis, has been implicated in the development of Th1 mediated immune diseases. Here we report a case of CD-like enteropathy in a patient receiving IFN-alpha for chronic myeloid leukaemia. Morphological assessment of duodenal biopsies taken from the patient showed total villous atrophy, crypt cell hyperplasia, and a high number of CD3+ intraepithelial lymphocytes. Both antigliadin antibodies and antiendomysial antibodies were positive. RNA analysis revealed pronounced expression of IFN-gamma. Withdrawal of gluten from the diet resulted in a patchy improvement in intestinal morphology, normalisation of laboratory parameters, and resolution of clinical symptoms. By western blot analysis, IFN-alpha protein was seen in the duodenal mucosa from untreated CD patients but not in controls. This was associated with marked expression of IFN-gamma protein in CD mucosa. Collectively, these results suggest a role for IFN-alpha in promoting Th1 responses to gluten.
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PMID:Role of interferon alpha in promoting T helper cell type 1 responses in the small intestine in coeliac disease. 1117 37

Primitive hematopoietic progenitors from some patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) express aberrant transcripts for interleukin 3 (IL-3) and granulocyte colony-stimulating factor (G-CSF), and exhibit autonomous proliferation in serum-free cultures that is inhibited by anti-IL-3 and anti-IL-3 receptor antibodies. Expression of the product of the Ph chromosome, the BCR/ABL oncogene, in mice by retroviral bone marrow transduction and transplantation induces CML-like leukemia, and some leukemic mice have increased circulating IL-3, and perhaps granulocyte-macrophage colony-stimulating factor (GM-CSF). These observations raise the possibility of autocrine or paracrine cytokine production in the pathogenesis of human CML. Mice with homozygous inactivation of the Il-3 gene, the Gm-csf gene, or both, were used to test the requirement for these cytokines for induction of CML-like disease by BCR/ABL. Neither IL-3 nor GM-CSF was required in donor, recipient, or both for induction of CML-like leukemia by p210 BCR/ABL. Use of novel mice deficient in both IL-3 and GM-CSF demonstrated that the lack of effect on leukemogenesis was not due to redundancy between these hematopoietic growth factors. Analysis of cytokine levels in leukemic mice where either donor or recipient was Il-3(-/-) indicated that the increased IL-3 originated from the recipient, suggestive of a host reaction to the disease. These results demonstrate that IL-3 and GM-CSF are not required for BCR/ABL-induced CML-like leukemia in mice and suggest that autocrine production of IL-3 does not play a role in established chronic phase CML in humans.
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PMID:Interleukin 3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL. 1122 92

Bcr/abl fusion gene, in experimental models, induces survival to growth factor deprivation and hypersensitivity to IL3. However, conflicting data were reported about chronic myeloid leukemia (CML) progenitors. We investigated the responsiveness of purified CML CFU-GM to GM-CSF/IL3 and their survival to growth factor deprivation. CFU-GM hypersensitivity to IL3 and/or GM-CSF was found in 3/11 CML cases only. CML CFU-GM survived well in stroma-free 'mass' culture (5 x 10(4) cells/ml) without cytokine addition, up to day 11, average recovery being around 95% in medium + 10% fetal bovine serum and 67-81% in serum-free medium. Conversely, normal progenitors declined steadily, particularly after extensive purification (18 +/- 10% recovery at the 7th day), and in serum-free medium (4 +/- 6% recovery). By contrast, normal and CML CFU-GM declined in a similar way in limiting dilution cultures (1-10 cells/50 microl). We also investigated the effects of retinoic acid and alpha-interferon on CFU-GM survival. Both all-trans- and 13-cis retinoic acid, particularly in combination with alpha-interferon, reduced CML CFU-GM recovery down to normal progenitors' values. In conclusion, hypersensitivity to CSFs is rare in CML, whereas resistance to growth factor deprivation has been confirmed in mass, but not in limiting, dilution cultures. Both stereoisomers of retinoic acid, at therapeutic concentrations and in combination with alpha-interferon, can overcome the survival advantage of CML progenitors.
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PMID:Growth advantage of chronic myeloid leukemia CFU-GM in vitro: survival to growth factor deprivation, possibly related to autocrine stimulation, is a more common feature than hypersensitivity to GM-CSF/IL3 and is efficiently counteracted by retinoids +- alpha-interferon. 1123 66

The role of the host immune compartment in the control of chronic myeloid leukaemia (CML) has been suggested by numerous biological and clinical evidence. In the present study, the phenotypic and functional machinery of both T and cytotoxic lymphocytes was evaluated in a series of CML patients in complete haematological, and frequently also in cytogenetic, remission after treatment with interferon (IFN) alpha or hydroxyurea, and compared with the profile observed in patients at diagnosis and in normal controls. In particular, the lymphocyte subset distribution, the cytotoxic activity and the intracellular production of tumour necrosis factor (TNF)alpha and IFN gamma by CD4(+), CD8(+) and CD56(+) cells were investigated. CML patients in complete haematological remission showed a normalized CD4/CD8 T-cell subset distribution, as well as a restored spontaneous and interleukin 2 (IL-2) induced cytotoxic function compared with the pattern observed at diagnosis. This was associated with a significantly increased proportion of activated CD4(+) lymphocytes (CD25(+)). TNF alpha and IFN gamma production by CD4(+), CD8(+) and CD56(+) lymphocytes was significantly enhanced compared with that of patients at diagnosis. However, the values were lower than those of normal controls. These results indicate that, in contrast to the observations at presentation, CML patients, at the time of the best possible response to treatment, show a normalized T-cell subset distribution associated with an activated CD4 T-cell compartment and a restored cytotoxic activity. In addition, they also show a markedly increased intracellular cytokine production by the lymphoid populations that play an important role in the process of specific tumour recognition. The design of therapeutic strategies aimed at stimulating the host immune compartment finds a further rationale for CML patients responsive to treatment with both IFN alpha and hydroxyurea.
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PMID:Phenotypic and functional characterization of the host immune compartment of chronic myeloid leukaemia patients in complete haematological remission. 1132 93

We report here a 75-year-old man from South France who developed Kaposi's Sarcoma (KS) 5 months after diagnosis of Philadelphia-chromosome positive chronic myelogenous leukemia (CML). He was found positive for HHV-8 by PCR, negative for both HIV 1 and HIV 2 by serology, and had a normal CD4/CD8 ratio. Favourable evolution of both CML and KS has been obtained with vinblastine and interferon alpha treatment. The patient is currently alive in complete remission of SK and major cytogenetic remission of CML with a 48 month follow-up. Since no immune deficiency could be documented in the patient, this rare observation suggests that CML may have triggered the onset of SK through cytokine release.
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PMID:Simultaneous occurrence of kaposi's sarcoma and chronic myelogenous leukemia. 1137 57

Although allogeneic transplantation is a curative therapy for chronic myeloid leukemia (CML), treatment-related mortality is still a major cause of posttransplantation mortality, especially for patients older than 40 years. We investigated, in a phase II trial, the role of a low-dose (550 cGy) high-dose rate (35 cGy/min) single-exposure total body irradiation (TBI) conditioning regimen for allogeneic peripheral blood stem cell (PBSC) transplantation in patients with CML. Between June 1997 and August 2000, 30 adult patients with CML underwent cytokine-mobilized allogeneic PBSC transplantation from HLA-matched siblings following administration of cyclophosphamide (60 mg/kg per day intravenously on days -2 and -1) and single-dose TBI (550 cGy delivered at 30 cGy/min on day 0). Cyclosporine A alone was administered for prophylaxis against graft-versus-host disease (GVHD). Median patient age was 47 years (range, 21-63 years), with 23 patients (77%) older than 40 years. The preparative regimen was well tolerated. Grade 4 toxicities and oral mucositis were not observed. Graft failure did not occur. Severe acute GVHD was observed in 5 patients (17%). The median follow-up was 23 months (range, 6-39 months). Cytogenetic or hematologic relapse was detected in 3 patients (10%), 2 of whom subsequently entered remission following a taper of immunosuppression. Nonrelapse mortality occurred in 5 patients (17%), and the Kaplan-Meier estimate of survival at 2 years was 83% (95% confidence interval, 70%-97%). In summary, this low-dose TBI-based preparative regimen resulted in uniform donor engraftment, with markedly reduced organ toxicity and nonrelapse mortality, in this relatively older cohort of patients with CML.
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PMID:Low incidence of transplantation-related acute complications in patients with chronic myeloid leukemia undergoing allogeneic stem cell transplantation with a low-dose (550 cGy) total body irradiation conditioning regimen. 1146 78


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