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)

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.
J Interferon Cytokine Res 1998 Oct
PMID:Local cutaneous necrotizing lesions associated with interferon injections. 980 17

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.
Cytokine 2000 Jul
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.
J Interferon Cytokine Res 2000 Jun
PMID:Retroviral coexpression of IFN-alpha and IFN-gamma genes and inhibitory effects in chronic myeloid leukemia cells. 1088 14

Interferon (IFN) consensus sequence binding protein (ICSBP)/IFN regulatory factor (IRF)-8 is an IFNgamma-inducible transcription factor of the IRF family and regulates transcription through multiple target DNA elements, such as IFN-stimulated response element (ISRE), Ets/IRF composite element, and IFN-gamma activation site (GAS). ICSBP(-/-) mice are immunodeficient and susceptible to various pathogens. They have defects in the macrophage function, including the ability to induce interleukin-12 (IL-12) p40 and some IFN-gamma-responsible genes. In addition, ICSBP(-/-) mice develop a chronic myelogenous leukemia (CML)-like syndrome, where a systemic expansion of granulocytes is followed by a fatal blast crisis. ICSBP(-/-) mice harbor an increased number of myeloid progenitor cells, and the -/- progenitors preferentially give rise to granulocytes, although they cannot efficiently generate another descendant of the myeloid lineage, macrophages. Studies with myeloid progenitor cells have shown that ICSBP drives their differentiation toward macrophage, whereas it inhibits granulocyte differentiation. Furthermore, myeloid cells from ICSBP(-/-) mice are resistant to apoptosis. These results illustrate the mechanism by which the loss of ICSBP leads to immunodeficiency and CML-like syndrome and suggest ICSBP's critical role in the development of myeloid cells.
J Interferon Cytokine Res 2002 Jan
PMID:ICSBP/IRF-8: its regulatory roles in the development of myeloid cells. 1184 85

Proliferative response of blast clonogenic cells to various hematopoietic growth factors (HGF), including stem cell factor (SCF) and flt3 ligand (FL) was investigated in 100 patients with acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) in myeloid crisis (MC). The frequency of spontaneous colony formation was significantly high in CML in MC (55%) and AML French-American-British (FAB) subtype M4 (48%) compared with M2 (16%). No spontaneous colony was formed in any of the patients with M1 and M3. The frequency of proliferative response to various HGF alone and in combination according to FAB subtype and CML in MC was as follows: that to granulocyte colony-stimulating factor (G-CSF) was lowest in M1 and CML in MC (50%) compared with other FAB subtypes (>or=86%), that to granulocyte-macrophage CSF (GM-CSF) was lowest in CML in MC (44%) compared with FAB subtypes (>or=74%), and that to interleukin-3 (IL-3) was lowest in CML in MC (30%) compared with FAB subtypes (>or=78%). SCF and FL stimulated blast colony formation in 11% and 17% of patients with M3, respectively, but there was no response to both, and in 60% and 57% of patients with CML in MC, respectively, with 14% showing a response to both. The frequency of proliferative response to both SCF and FL increased in the order of M1 (33%), M2 (63%), M4-5 (95%), and M6 (100%). The results are summarized as follows: absence of spontaneous colony formation and response to HGF other than SCF and FL, designated as HGF-dependent growth (M3); spontaneous colony formation and lowest response to HGF, designated as autonomous growth (CML in MC); and spontaneous colony formation and highest response to HGF including SCF and FL, designated as autocrine growth (M4-6). M1 and M2 were intermediate between CML in MC and M4-6. The relation between in vitro growth pattern of blast clonogenic cells and prognosis in AML FAB subtype and CML in MC is discussed.
J Interferon Cytokine Res 2002 Mar
PMID:Differential response to stem cell factor and Flt3 ligand by the FAB subtype in acute myeloid leukemia clonogenic cells. 1203 41

Cytokine-mobilized peripheral blood is increasingly used instead of bone marrow as the source of cells for allogeneic transplantation. Although cells lead to faster hematologic recovery, their effects on graft-versus-host disease, relapse, and survival are less certain. Between January 1996 and February 2000, 228 patients with chronic myeloid leukemia, acute myeloid leukemia, or myelodysplasia were randomized to receive either bone marrow or peripheral blood allografts from HLA-matched siblings. All patients received busulfan and cyclophosphamide as conditioning chemotherapy and cyclosporine and methotrexate as graft-versus-host disease prophylaxis. We compared the times to neutrophil and platelet recovery, acute and chronic graft-versus-host disease, relapse, and overall survival between the groups. The median times to neutrophil recovery were 19 days and 23 days and the times to platelet recovery were 16 days and 22 days in the peripheral blood and bone marrow groups, respectively (P <.0001 for both comparisons). The cumulative incidence of grades II to IV acute graft-versus-host disease 100 days after transplantation was 44% in both groups (hazard ratio, 0.99; 95% confidence interval, 0.66-1.49; P >.9), and the incidence of extensive chronic graft-versus-host disease at 30 months after transplantation was 40% with peripheral blood and 30% with bone marrow (hazard ratio, 1.23; 95% confidence interval, 0.78-1.96; P =.37). There was no statistically significant difference in the probability of relapse of the underlying disease between the groups. The probabilities of survival at 30 months after transplantation were 68% and 60% in the peripheral blood and bone marrow groups, respectively (hazard ratio, 0.62; 95% confidence interval, 0.39-0.97; P =.04). In patients with chronic myeloid leukemia, acute myeloid leukemia, and myelodysplasia undergoing allogeneic transplantation from matched siblings, the use of peripheral blood instead of bone marrow leads to faster hematologic recovery, similar risk of graft-versus-host disease, and improved survival.
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PMID:A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. 1217 66

We have combined in vitro clonogenic culture and a highly sensitive stain for haemoglobin to compare the influence of EPO, IL-3, SCF, TGFbeta1, MIP-1alpha and IFNgamma, to directly stimulate cells in the progenitor compartment to develop towards the erythroid lineage. Three cell lines were chosen, as they exist developmentally arrested in the progenitor compartment, yet in a pliant state of maturation. HEL (erythroleukaemia) and K562 (CML-derived) cell lines, may, under appropriate stimuli, develop erythroid characters, whilst the third, U937 (as control cell line), may be stimulated by DMSO to differentiate to myeloid cells. After in vitro semi-solid methylcellulose culture with these cytokines, resulting colonies were stained with 2,7-diaminofluorene (DAF), which sensitively stains haemoglobin blue. Haemoglobin production was low in HEL and K562 cells and absent in U937. Cytokine analysis showed varying levels of influence depending on the starting level of cell line maturation. EPO and TGFbeta1 maximally stimulated haemoglobin production in the HEL and K562 cell lines. This differential cytokine stimulation analysis combined with sensitive DAF haemoglobin detection could be applied in the study of many erythropoiesis-deficient patients or primitive erythropoiesis.
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PMID:Diaminofluorene stain detects erythroid differentiation in immature haemopoietic cells treated with EPO, IL-3, SCF, TGFbeta1, MIP-1alpha and IFNgamma. 1258 Nov 92

Cytokine-provided survival signals are known to suppress apoptosis through inhibition of mitochondrial pathways that involve Bcl-2 family members. Here we show that in hematopoietic cells, cytokines also regulate death receptor-mediated pathways. We demonstrate that hematopoietic cytokines such as IL-3 and erythropoietin in normal cells, as well as BCR-ABL oncoprotein in transformed cells, inhibit transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Using small interfering RNAs, we show that the inhibition of TRAIL function is sufficient to partially rescue cytokine-deprived cells from apoptosis. Finally, we demonstrate that cytokine and BCR-ABL suppression of TRAIL transcription is mediated through phosphorylation and inhibition of the forkhead FOXO3a transcription factor. BCR-ABL-induced inhibition of TRAIL transcription in hematopoietic cells may provide a novel mechanism for tumorigenicity in chronic myeloid leukemia.
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PMID:Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. 1275 Apr 77

There is a strong graft-versus-leukemia (GVL) effect of allogeneic stem cell transplantation (SCT) due to elimination of tumor cells by alloimmune effector lymphocytes. When leukemia relapses after allogeneic SCT, donor lymphocyte transfusions (DLTs) can induce sustained remissions in some patients. This review summarizes the current status on clinical use of DLT, the basis of GVL reactions, problems associated with this therapy, and new strategies to improve DLT. Several multicenter surveys demonstrated that the GVL effect of DLT is most effective in chronic myelogenous leukemia (CML), whereas it is less pronounced in acute leukemia and myeloma. Cytokine stimulation to induce differentiation of myeloid progenitor cells or to up-regulate costimulatory molecules on tumor cells may improve the efficacy of DLT. Infections and graft-versus-host disease (GVHD) are major complications of DLT. Control of GVHD may be improved using suicide gene-modified T cells for DLT, allowing T-cell elimination if severe GVHD develops. Hopefully, in the future, GVL effect can be separated from GVHD through adoptive transfer of selected T cells that recognize leukemia-specific antigens or minor histocompatibility antigens, which are expressed predominantly on hematopoietic cells, thereby precluding attack of normal tissues. In patients with leukemia and lymphomas with fast progression, tumor growth may outpace development of effector T cells. Here it may be preferable to select stem cell transplant donors with HLA-mismatches that allow alloreactive natural killer cells, which appear early after transplantation, to retain their cytolytic function. New approaches for adoptive immune therapy of leukemia, which promise a better prognosis for these patients, are being developed.
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PMID:Graft-versus-leukemia reactions in allogeneic chimeras. 1295 64

Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes (CTL) with the characteristic CD3+CD56+ phenotype. These cells have demonstrated higher proliferative and cytolytic activities in comparison to the reported CD3-CD56+ lymphokine activated killer (LAK) cells that are essentially activated natural killer (NK) cells. CIK cells are non-MHC-restricted in target cell recognition and killing. We have shown the feasibility of generating CIK cells from a series of marrow samples of patients with acute myeloid leukemia (AML) collected at diagnosis. At maturity, the CIK cells exhibit potent cytotoxicity against autologous AML targets as well as allogeneic myeloid leukemia cells, regardless of the HLA types of these targets. This observed cytotoxicity is not entirely due to NK cells as prior pre-absorption of the NK cells cytolytic activities does not abolish the subsequent cytotolytic activities against leukemic targets. It has also been reported by others that CIK cells are cytolytic against chronic myeloid leukemia (CML) cells, both in vitro and in the SCID mouse tumor model. In a mouse transplant model across MHC barrier, the CIK cells generated from the donor do not induce graft vs. host disease as observed for unfractionated donor splenocytes. In comparison to untreated control mice, the infusion of CIK cells results in the prolonged survival of murine leukemia-bearing mice. CIK cells also express CD94, part of the NK receptor comprising of CD94-NKG2 heterodimer. However, only low level of the killer immunoglobulin-like receptors are expressed by the CIK cells. In addition, as reported for the classical CTL, CIK cells could interact with dendritic cells (DC) to result in the enhancement of cytotolytic activities against tumor cells. The characteristic biological properties of the CIK cells would, therefore, enable them to be exploited for anti-leukemic therapy.
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PMID:Cytokine-induced killer cells: NK-like T cells with cytotolytic specificity against leukemia. 1456 44


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