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)

An important step in the oncogenic transformation of hemopoietic cells and the subsequent development of leukemia is the proliferation of tumor cells in the absence of exogenous growth factors. In most cases of chronic myelocytic leukemia and in some cases of acute myelocytic leukemia and acute lymphocytic leukemia, the bcr-abl oncogene is involved in this process. Although the BCR-Abl oncoprotein demonstrates enhanced tyrosine kinase activity in leukemic cells, the mechanism by which this leads to growth factor independence remains poorly defined. One proposed mechanism is the activation of cytokine signal transduction pathways, possibly by an autocrine loop involving IL-3 and/or granulocyte-macrophage CSF. Examination of several different cell lines expressing BCR-Abl demonstrates that some of these cells have constitutive activation of the JAK/STAT signaling pathway. We have found the constitutive activation of STAT5 in most, but not all, cell lines expressing BCR-Abl. This constitutive activation of STAT5 is variably associated with a corresponding activation of JAK kinases. Ab blocking studies show that the activation of STAT5 in these cell lines cannot be attributed to the activation of an IL-3/granulocyte-macrophage CSF-driven autocrine loop. Interestingly, samples of peripheral blood cells derived from patients with acute myelocytic leukemia and chronic myelocytic leukemia, which express BCR-Abl, demonstrate constitutive activation of STAT family members. These studies suggest that in a variety of leukemic states, BCR-Abl may use a bypass mechanism to activate cytokine signal transduction pathways.
 ...
PMID:Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. 936 95

Fifteen patients with hematological malignancies [9 acute nonlymphoblastic leukemia (ANLL), four chronic myelogenous leukemia (CML), two acute lymphoblastic leukemia (ALL)] received allogeneic peripheral blood stem cell transplantation (alloPBSCT) from HLA-identical sibling donors. Donors received 2.5-15 micrograms/kg/day of recombinant human granulocyte colony stimulating factor (rhG-CSF) for 5-10 days. Administration of rhG-CSF was well tolerated except for mild to moderate bone pain occurring in all the donors which was relieved by oral paracetamol. A total of 40 leukaphereses were performed for the 15 donors using the bilateral antecubital veins. None of the donors needed central venous line insertion. The median number of apheresis procedures for each patient was 3 (2-3). A median of 7.7 (4-38.2) x 10(8)/kg mononuclear cells, 35 (2.4-90.0) x 10(6)/kg CD34+ cells, 1.85 (0.45-4.8) x 10(8)/kg CD3 and 0.3 (0.16-1.01) x 10(8)/kg natural killer cells were given without any manipulation. Cyclosporin A (CsA) plus short-course methotrexate (MTX) (12 patients) and CsA alone (3 patients) were used for graft versus host disease (GVHD) prophylaxis. Median granulocyte and platelet engraftments were done on days 11 (10-31) and 16 (11-54) respectively. Grades II-IV GVHD occurred in 62% of the patients and grades III-IV in 15%. Twelve patients are still alive with full engraftment and disease-free. In conclusion, alloPBSCT is an alternative to allogeneic bone marrow transplantation, because of the ease of collection and rapid hematological recovery. However, there is a trend for increased acute GVHD in our leukemia patients compared to allogeneic bone marrow.
 ...
PMID:Allogeneic peripheral blood stem cell transplantation: is there an increased risk of graft vs host disease in leukemia patients? 937 93

Coexistence of Philadelphia chromosome (Ph)-negative, primitive hematopoietic progenitor cells with their malignant counterparts in chronic myelogenous leukemia (CML) has been reported. As most of the Ph-negative progenitor cells do not express the HLA-DR antigen, selection of them might be possible. Peripheral blood progenitor cells (PBPC) from eight early chronic phase (CML) patients were mobilized by ICE chemotherapy followed by simultaneous administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human interleukin 3 (rhIL-3). PBPCs were collected by leukapheresis in the early phase of hematopoietic recovery after chemotherapy, CD34 selected and cultured in vitro. The content of Ph chromosome-positive cells in leukapheresis products as well as after CD34 enrichment and after in vitro culture was analyzed by interphase fluorescence in situ hybridization (FISH) and RT-PCR. The percentage of Ph chromosome-positive PBPC was reduced after each purification step in almost all samples. A substantial number of PBPC samples were negative for the bcr/abl mRNA rearrangement as analyzed by RT-PCR. The present study demonstrates the feasibility of mobilizing Ph-negative PBPC during the early phase of hematopoietic recovery after ICE chemotherapy and simultaneous administration of rhIL-3 and rhG-CSF.
 ...
PMID:Quality of IL-3 and G-CSF-mobilized peripheral blood stem cells in patients with early chronic phase CML. 952 27

We previously suggested that using a combined conditioning regimen including rhG-CSF with allogeneic BMT in refractory AML and CML in blast crisis might reduce the rate of relapse and improve disease-free survival, without any major side effects. In this study, we used the same protocol for 10 AML patients in complete remission (CR) and 6 CML patients in the chronic phase (CP). We compared disease-free survival as well as toxic side effects of the regimen with 6 AML patients in CR and 6 CML patients in CP treated with chemoradiotherapy without G-CSF. The conditioning regimen consisted of TBI and high-dose AraC. RhG-CSF was infused continuously at a dose of 5 microg/kg/day, starting 24 hr before the initial dose of total body irradiation (TBI) until the end of AraC therapy. In all 28 cases, there were no early stage deaths due to regimen-related toxicity (RRT). None of the 10 AML cases treated with the G-CSF combined regime relapsed. In 6 AML cases treated conventionally without G-CSF, one patient died of infection and another relapsed. There were no relapses in either CML group. In the combined G-CSF group, one patient died of interstitial pneumonitis 48 days after BMT, while the rest of the CML cases are still alive. There were no relapses with rhG-CSF and no serious adverse effects in terms of RRT, acute graft vs. host disease (GVHD), or leukocyte recovery.
 ...
PMID:Recombinant human granulocyte colony-stimulating factor (G-CSF) combined conditioning regimen for allogeneic bone marrow transplantation (BMT) in standard-risk myeloid leukemia. 954 74

This study aimed to demonstrate that sufficient Ph-negative blood progenitors could be collected following administration of glycosylated rhG-CSF (lenograstim) to patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukaemia (CML) who responded to recombinant alpha-interferon (alpha-IFN) (Ph-positive marrow metaphases < 35%). 23 patients received lenograstim (150 microg/m2) once daily for a median of 9 d. Peak circulating numbers of white blood cells (36.4 x 10(9)/l), CD34+ cells (24/ microl) and colony-forming unit-granulocyte-macrophage (CFU-GM; 1346.5/ml) occurred at a median of day 8, day 8 and day 7, respectively. Two to six (median three) leukaphereses (LK) were performed from days 5 to 12. The median number of mononuclear cells (MNC), CD34+ cells and CFU-GM collected per patient was 7.35 x 10(8/)kg, 2.72 x 10(6)/kg and 10.23 x 10(4)/kg, respectively. 22/23 patients had LK which contained either 10(4) CFU-GM/kg and/or 10(6) CD34+ cells/kg; 47LK (from 20/22 patients) were evaluable for cytogenetics. The median percentage of Ph-positive cells was 0, and 43/47 LK (91%) contained <35% Ph-positive cells; 25 (53%) were entirely negative. Sixteen of 20 evaluable patients had one or more LK with <35% Ph-positive cells, and 12 had at least one 100% Ph-negative LK. Mobilization and collection of Ph-negative cells were not influenced by the dose or duration of alpha-IFN administration before (or during) lenograstim administration or by the quality of cytogenetic response (complete v major) during lenograstim administration. No significant side-effects were observed. Thus, lenograstim administration can result in satisfactory Ph-negative blood progenitor cell collection. Autologous transplantation of such cells may be used when indicated.
 ...
PMID:Collection of Ph-negative progenitor cells with granulocyte-colony stimulating factor in patients with chronic myeloid leukaemia who respond to recombinant alpha-interferon. 972 88

We investigated tyrosine phosphorylation of proteins in primary human leukemia cells stimulated by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), tumor necrosis factor (TNF), thrombopoietin (TPO) and phorbol myristate acetate (PMA) in 61 patients with acute myeloid leukemia (AML), nine patients with chronic myeloid leukemia (CML) in blastic crisis and four patients in chronic phase, and compared these data of leukemia with those of normal human immature hematopoietic cells. These cytokines and PMA induced tyrosine phosphorylation of proteins in a manner characteristic for each cytokine or PMA in AML cells. G-CSF, GM-CSF and IL-3 frequently phosphorylated p92, p80, p70, p44 and p42. p95 was frequently phosphorylated by G-CSF, and was phosphorylated in one third of the cases by TPO. On the other hand, TNF selectively induced tyrosine phosphorylation of p42, and PMA selectively induced that of p44 and p42. In marked contrast to AML cells, CML cells responded poorly to cytokines with protein tyrosine phosphorylation, and normal human bone marrow mononuclear cells and CD34-positive cells also showed poor response to cytokines. The results of the immunoprecipitation studies showed tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5 induced by G-CSF, GM-CSF, IL-3 and/or TPO in six cases, that of extracellular signal-regulated kinase (ERK) by GM-CSF in two cases and that of p38 by TNF in three cases. Intracellular amount of Stat5 was markedly increased in AML cells compared with that in CML cells and normal human bone marrow cells. whereas intracellular amount of ERK and p38 was uniformly abundant in both leukemic and normal cells. These results show cytokine-specific and amplified tyrosine phosphorylation of proteins in AML cells and suggest that amplified response might, at least in part, result from the increased amount of signaling molecules such as Stat5.
 ...
PMID:Tyrosine phosphorylation of proteins in primary human myeloid leukemia cells stimulated by cytokines: analysis of the frequency of phosphorylation, and partial identification and semi-quantification of signaling molecules. 988 38

We present a case of death likely to be directly due to cyclosporine (CsA) neurotoxicity. To date, there have been no reports of deaths directly due to CsA neurotoxicity, nor has an associated histological lesion been described independent of confounding processes. A 54-year-old male received an HLA-matched-unrelated BMT for CML. He developed progressive encephalopathy and on day +79 had a generalized seizure. All CSF studies were negative for infectious causes. MRI revealed diffuse, symmetrical white matter abnormalities located in the occipital sub-cortex, thalamus, mid brain, pons, and cerebellum which were typical of CsA toxicity. The patient died of central respiratory failure within 72 h of discontinuing CsA. Autopsy revealed diffuse patchy white matter edema and astrocytic injury without evidence of axonopathy, demyelination, microvascular injury, or infectious/inflammatory process. This case demonstrates previously undescribed lethal CsA neurotoxicity and may reveal an associated primary pathological lesion.
 ...
PMID:Fatal outcome due to cyclosporine neurotoxicity with associated pathological findings. 1019 8

We report on a patient with Klinefelter's syndrome who underwent successful syngeneic peripheral blood stem cell transplantation (PBSCT) for chronic myelogenous leukemia (CML). A-46-year-old man was given a diagnosis of chronic phase CML in May 1994 on the basis of findings of leukocytosis (54,000/microliter) and bone marrow chromosomal abnormalities [47, XXY, t(9; 22; 14) (q34; q11; q24)]. Hydroxyurea and interferon alpha were administered. In August 1996, a syngeneic transplant was performed following myeloablative therapy, using peripheral blood stem cells collected from the patient's identical twin brother, who had been pretreated with rhG-CSF. Following transplantation (4.0 x 10(6) CD34+ cells/kg) and the subsequent administration of rhG-CSF, the patient rapidly achieved normal tri-lineage hematopoiesis. A post-transplant chromosomal analysis of the patient's bone marrow cells detected the 47, XXY karyotype. Although the major BCR-ABL gene had been detected in bone marrow by RT-PCR methods prior to the syngeneic PBSCT (August 1996), it was not detected after PBSCT (January 1997). In March 1998, interphase fluorescence in situ hibridization (FISH) procedures disclosed XXY signal patterns in peripheral blood lymphocyte samples from the patient and donor, at frequencies of 96% and 97%, respectively. Both the patient and donor had high levels of serum FSH and LH and low levels of serum testosterone.
 ...
PMID:[Syngeneic peripheral blood stem cell transplantation for chronic myelogenous leukemia associated with Klinefelter's syndrome]. 1022 29

A novel Philadelphia chromosome-positive cell line was established from the peripheral blood of a patient with chronic myelogenous leukemia in megakaryoblastic crisis. This cell line, designated TN922 showed the positive phenotypes for myeloid, monocyte-macrophage, erythroid and megakaryocytic markers. The stimulation with phorbol 12-myristate 13-acetate (PMA) increased the expression of megakaryocytic markers including the platelet peroxidase activity, dimethylsulfoxide or transforming growth factor-beta promoted up-regulation of the erythroid markers. Stimulation with PMA, tumor necrosis factor-alpha or interleukin-6 also brought about the expression of monocytoid markers. These findings indicated that TN922 cell line has the property of acting as multipotential progenitor cells. TN922 cells showed gradual growth in the absence of growth factors but the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) promoted cell growth. The message of GM-CSF was detected in TN922 cells and the neutralizing antibody against GM-CSF receptor alpha-subunit suppressed cell growth. These results indicated that TN922 cell line proliferates in an autocrine secretion of GM-CSF.
 ...
PMID:A novel Philadelphia chromosome-positive cell line with multipotential properties. 1022 66

This paper reports 3 cases of allogeneic peripheral blood stem cell transplantation (Allo-PBSCT) for the patients with chronic myeloid leukemia (CML). The patients received MMC preparative regimen with high dose chemotherapy (Melphalan 170 mg/m2, p.o. on Day-5, MeCCNU 400 mg/m2, p.o. on Day-4, and Cyclophosphomide 60 mg/kg/day, i.v. on Days-3 and -2). The HLA-identical sibling donors received filgrastim (rhG-CSF) for mobilization at a dose of 300 micrograms/day for 6 days. Leukaphereses were done at the 6th day of mobilization. A median of 8000 ml (2 times total blood volume) of blood was processed the collecting: 2.5-4.5 x 10(8)/kg MNC, 12.8-20.0 x 10(6)/kg CD34+ cells (including 4.8-7.5 x 10(6)/kg CD34+CD33-, 8.0-13.0 x 10(6)/kg CD34+CD33+), and 3.5-4.3 x 10(5)/kg CFU-GM. Cyclosporin A and methotrexate were used for GVHD prophylaxis. Hematopoitic function recovered as for 14-20 days to > 0.5 x 10(9)/L of neutrophil count, and for 16-34 days to > 20 x 10(9)/L of platelet count. At day + 100, chromosome analysis of bone marrow cells showed that complete chimera without ph1 positive chromosome in Cases 1 and 3, and a partial chimera with 73% donor karyotype in Case 2. All patients now are in disease free survival. No episode of acute graft versus host disease (GVHD) developed. It was concluded that HLA matched sibling allogeneic PBSCT result in rapid hematopoitic reconstitution and the MMC conditioning regimen is effective both in leukemic cells eradication and in immunosuppression for stem cells engraftment, and the drug related toxicity could be tolerated by patients.
 ...
PMID:[MMC conditioning regimen (Melphalan, MeCCNU and cyclophosphamide) followed by allogeneic peripheral blood stem cells transplantation for chronic myeloid leukemia]. 1074 39


<< Previous 1 2 3 4 5 6 7 8 9 Next >>