Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was the objective of the study to characterize CD34+ hematopoietic progenitor cells from peripheral blood (PB) and bone marrow (BM) in a group of 24 cancer patients. After cytotoxic chemotherapy, R-metHu granulocyte colony-stimulating factor (R-metHuG-CSF; filgrastim, 300 micrograms daily, subcutaneously) was given to shorten the time of neutropenia as well as to increase the rebound of peripheral blood progenitor cells (PBPC) for harvesting. The proportion of CD34+ cells in the leukapheresis products (LPs) was 1.4-fold greater than in BM samples that were obtained at the same day (LP: median, 1.4% v BM: median, 1.0%, P < .01). Two- and three-color immunofluorescence showed that blood-derived CD34+ cells comprised a greater proportion of a particular early progenitor cell than CD34+ cells of bone marrow. Blood-derived progenitor cells tended to have a higher mean fluorescence intensity of CD34 and expressed significantly lower levels of HLA-DR (mean fluorescence intensity of HLA-DR: 442.6 +/- 44.9 [LP] v 661.5 +/- 64.6 [BM], mean +/- SEM, P < .01). Furthermore, the blood-derived CD34+ cells comprised a 1.7-fold greater proportion of Thy-1+ cells (LP: median, 24.4% v BM: median, 14.4%, P < .001) and expressed significantly less c-kit (LP: median, 20.5% v BM: median, 31.0%, P < .01). Three-color analysis showed that high levels of Thy-1 expression were restricted to CD34+/HLA-DRdim or CD34+/HLA-DR- cells confirming the early developmental stage of this progenitor cell subset. The proportion of CD34+/CD45RA(bright) cells representing late colony-forming unit granulocyte-macrophage (CFU-GM) was smaller in LPs compared with BM (P < .05). For an examination of BM CD34+ cells before the mobilization chemotherapy, samples of 16 patients were available. The mean proportion of c-kit expressing CD34+ cells in the bone marrow during G-CSF-stimulated reconstitution decreased 1.8-fold compared with baseline values. There was no difference in the proportion of BM-derived CD34+/Thy-1+ cells and CD34+/CD45RA+ cells between steady-state hematopoiesis and G-CSF-supported recovery. Our data suggest that during G-CSF-enhanced recovery, CD34+ cells in the PB are enriched with more primitive progenitor cells to evenly replenish the BM after the chemotherapy-related cytotoxic damage.
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PMID:Blood-derived autografts collected during granulocyte colony-stimulating factor-enhanced recovery are enriched with early Thy-1+ hematopoietic progenitor cells. 753 95

The growth and differentiation of selected bone marrow CD34+ cells stimulated with hematopoietic growth factors in lipid cultures were evaluated to determine whether cell types that may be useful for reducing the neutropenia associated with high-dose chemotherapy (HDC) can be produced and quantitated in vitro. CD34+ cells enriched from bone marrow were cultured for up to 5 weeks in interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) with or without stem cell factor (SCF) (also termed c-kit ligand). The mixture of IL-3, GM-CSF and G-CSF resulted in an 18-fold increase in cells after 10 to 12 days of culture and a 94-fold increase after 21 days. A 3-fold increase in colony-forming unit granulocyte-macrophage (CFU-GM) was observed after 10 days of culture. The addition of SCF during the first 10 days of culture further augmented the proliferation of cell numbers to 24-fold and colony-forming cells (CFC) to 8-fold after 10 days while cell numbers increased 130-fold after 21 days. Two-color flow cytometry defined phenotypes expressing CD11b and CD15 that represented maturation stages of neutrophils. Maturation of neutrophils in these cultures could be followed by the initial appearance after 3 to 7 days of a CD15+CD11b- phenotype representing promyelocytes, which gave rise after 2 to 3 weeks to a CD15+CD11b+ phenotype representing more mature neutrophil forms (metamyelocytes to segmented neutrophils). In contrast to normal neutrophil development, only a small fraction (10 to 15%) of the culture-derived neutrophils expressed CD16. These data define the kinetics and differentiation of neutrophils and neutrophil precursors from selected CD34+ cells in liquid cultures.
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PMID:Expansion of neutrophil precursors and progenitors in suspension cultures of CD34+ cells enriched from human bone marrow. 768 2

Selected CD34+ cells from mobilized apheresis products were cultured in serum-free or serum-containing media supplemented with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and stem cell factor (SCF; c-kit ligand). We examined the emergence of a CD15+CD11b- population, which appeared morphologically to be promyelocytes. This CD15+CD11b- population can be further expanded in culture into morphologically mature granulocytes. In an attempt to characterize this culture-derived CD15+CD11b- promyelocytic population, single cells were clone sorted into wells of a Terasaki plate containing various growth factors. We compared the growth factor requirements and kinetics of this apheresis culture-derived CD15+CD11b- population to the CD15+CD11b- population from fresh bone marrow samples. Our studies indicate that the CD15+CD11b- promyelocytic population from bone marrow and blood are equivalent in their ability to proliferate and in their requirements for growth factors. The CD15+CD11b- population in vitro shows a high proliferative capacity when compared with the other CD15/CD11b populations (CD15-CD11b-, CD15+CD11b+, CD15-CD11b+). Thus, we can manipulate CD34+ cells in vitro to proliferate and differentiate toward a mature neutrophil lineage. The CD15+CD11b- promyelocytic population derived from this culture may represent the most effective cultured cell population for therapeutic reduction of neutropenia in vivo based on both its stage of differentiation and its proliferative potential.
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PMID:Characterization of a culture-derived CD15+CD11b- promyelocytic population from CD34+ peripheral blood cells. 933 18

SCF is a potent pro-proliferative cytokine crucial for haematopoiesis, which binds to c-kit and activates its tyrosine kinase activity. Inactivating mutations of either SCF or c-kit have been described in mice and lead to increased sensitivity to treatment with ionising radiation. Imatinib is a tyrosine kinase inhibitor with high affinity for c-Abl, PDGFR and c-kit. In this study we investigated the effect of concomitant administration of imatinib and idarubicin, an anthracycline with haematosuppressive activity, in nu/nu mice and murine bone marrow cells. Double-treated animals showed significantly increased mortality compared to mice that received imatinib or idarubicin alone only when idarubicin and imatinib were given simultaneously. The combined treatment induced a more severe neutropenia with a slower recovery when compared to mice treated with idarubicin alone. The myeloid metaplasia usually observed in the spleen after idarubicin treatment was absent in mice co-treated with imatinib. Bone marrow from double-treated animals also showed decreased numbers of megakaryocytes and myeloid precursor cells. In vitro culture of murine bone marrow cells in the presence of imatinib inhibited SCF-induced proliferation and recovery from treatment with idarubicin. Our results indicate that the simultaneous administration of imatinib enhances idarubicin-induced haematopoietic toxicity in vivo and in vitro.
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PMID:Effect of imatinib on haematopoietic recovery following idarubicin exposure. 1496 Oct 27

We describe a patient who had a metastatic gastrointestinal stromal tumor (GIST) after previous failed extensive therapy, including multiple surgeries and hepatic artery embolization. Within a few months of starting administration of imatinib mesylate, the patient exhibited a clinical response with grade 3 neutropenia, when pulmonary tuberculosis developed. A c-kit mutation in exon 11 was detected only in metastatic liver specimens. It is unclear whether or not pulmonary tuberculosis may be induced by imatinib mesylate treatment, but caution is warranted in immunocompromised GIST patients. This is the first report of tuberculosis associated with neutropenia during imatinib mesylate treatment.
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PMID:Malignant gastrointestinal stromal tumor of the small intestine complicated with pulmonary tuberculosis during treatment with imatinib mesylate. 1575 Feb 70

The levels of soluble c-kit ligand (sKL), also known as Steel factor or stem cell factor, were measured in blood serum and long-term bone marrow culture supernatants of 81 patients with chronic idiopathic neutropenia (CIN) and 22 normal controls using a commercially available enzyme-linked immunosorbent assay (ELISA). We found that the levels of serum and culture supernatant sKL did not differ significantly between patients and control subjects and that both serum and supernatant values of the cytokine did not correlate with the number of circulating neutrophils. Furthermore, we found that the levels of the culture supernatant granulocyte colony-stimulating factor (G-CSF), also measured by ELISA, were significantly increased in the patients compared to controls but individual G-CSF values did not correlate with the values of supernatant sKL. These findings suggest that sKL-producing cells continuously secrete sKL and that cytokine secretion is independent of the degree of neutropenia or the levels of supernatant G-CSF in patients with CIN.
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PMID:Soluble c-kit ligand production by bone marrow stromal cells is independent of the degree of neutropenia in patients with chronic idiopathic neutropenia. 1639 9

Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small molecule inhibitors of the VEGF pathway will likely have a positive impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to determine the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiographic response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small molecule inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.
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PMID:Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide. 2082 42

Neutropenia is common to both Hermansky-Pudlak syndrome type 2 and canine cyclic hematopoiesis (CH) which are caused by mutations in the AP3B1 gene. The purpose of this study was to determine if pearl mice were neutropenic. Complete blood counts (CBCs) and bone marrow differential counts, colony forming unit (CFU) assay, bone marrow lineage negative (lin(-)), Sca(+) and c-kit(+) cells (LSK cells), bone marrow elastase, myeloperoxidase, and cathepsin G enzyme activity were compared in C57Bl6 (Bl/6) and pearl mice. Stress granulopoiesis was evaluated following 200 mg/kg cyclophosphamide or 1 mg/kg bortezomib administration and by limiting dilution bone marrow transplantation. The CBCs and CFUs were determined in Bl/6 and pearl mice following AMD3100 or granulocyte colony-stimulating factor (G-CSF) administration. Pearl mice were not neutropenic and did not have cyclic neutropenia. Bone marrow elastase, myeloperoxidase, and cathepsin G enzyme activity were similar in pearl and Bl/6 mice. The numbers of CFU-G, CFU-GEMM, and LSK cells were increased moderately in pearl mice. Stress granulopoiesis was similar in Bl/6 and pearl mice. CFU assays and CBCs performed on Bl/6 and pearl mice administered AMD3100 resulted in similar results. However, normal mice administered G-CSF had higher peripheral blood neutrophil counts and greater CFU numbers compared with pearl mice. Unlike patients with HPS-2 and dogs with CH, pearl mice did not have neutropenia or CH but had decreased hematopoietic progenitor cell and granulocyte mobilization in response to G-CSF.
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PMID:Decreased hematopoietic progenitor cell mobilization in pearl mice. 2374 40

A 73-year-old man was found to have an intestinal tumor, approximately 10 cm in diameter, on computed tomography (CT). In September 2001, he underwent partial resection of the jejunum with partial colectomy and left nephrectomy. Pathological examination showed 2 mitoses per 50 high-power fields, and immunohistochemical analysis showed positive staining for c-kit. Based on the above findings, the tumor was diagnosed as a high-risk malignant gastrointestinal stromal tumor( GIST) of the small intestine; the patient was followed up and no adjuvant therapy was administered. In October 2005, an abdominal CT scan revealed 2 tumors with diameters of 21 and 28 mm in the S8 and S7 region of the liver, respectively, and the patient was diagnosed with liver metastases from GIST. After obtaining adequate informed consent, chemotherapy with imatinib (400 mg/day) was initiated. Although the patient experienced partial response (PR) 2 months after the treatment, grade 3 neutropenia and general fatigue were observed. Therefore, the treatment schedule was changed to 1 week of therapy, followed by 1 week of rest. At present, at 91 months after the diagnosis of liver metastases, the patient shows no signs of recurrence. Therefore, it is important that adjuvant chemotherapy should be considered for the treatment of patients with high-risk malignant GIST.
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PMID:[A case of multiple liver metastases after resection of gastrointestinal stromal tumor of the small intestine that was successfully treated with imatinib mesylate]. 2439 96

Genome sequencing studies of patient samples have implicated the involvement of various components of the epigenetic machinery in myeloid diseases, including the de novo DNA methyltransferase DNMT3A. We have recently shown that Dnmt3a is essential for hematopoietic stem cell differentiation. Here, we investigated the effect of loss of Dnmt3a on hematopoietic transformation by forcing the normally quiescent hematopoietic stem cells to divide in vivo. Mice transplanted with Dnmt3a-null bone marrow in the absence of wildtype support cells succumbed to bone marrow failure (median survival, 328 days) characteristic of myelodysplastic syndromes with symptoms including anemia, neutropenia, bone marrow hypercellularity, and splenomegaly with myeloid infiltration. Two out of 25 mice developed myeloid leukemia with >20%blasts in the blood and bone marrow. Four out of 25 primary mice succumbed to myeloproliferative disorders, some of which progressed to secondary leukemia after long latency. Exome sequencing identified cooperating c-Kit mutations found only in the leukemic samples. Ectopic introduction of c-Kit variants into a Dnmt3a-deficient background produced acute leukemia with a short latency (median survival, 67 days). Our data highlight crucial roles of Dnmt3a in normal and malignant hematopoiesis and suggest that a major role for this enzyme is to facilitate developmental progression of progenitor cells at multiple decision checkpoints.
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PMID:Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation. 2561 34


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