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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phenotypic and biologic properties of malignant cells in a case of aggressive mastocytosis with multi-organ involvement, circulating mast cell precursors and absence of skin infiltrates were analyzed. Circulating mast cell precursors were detected by immunostaining using antibodies against mast cell tryptase as well as by electron microscopy. These progenitors were tryptase+/chymase- (MCT) and accounted for 10 to 20% of nucleated mononuclear blood cells (MNC). A subset of them contained metachromatic granules. As assessed by combined toluidine blue/immunofluorescence staining, the granulated mast cell precursors were found to express CD9 (P24), CD33 (gp67) and CD44 (Pgp-1), but not basophil-related markers (CD11b (C3biR), CDw17 (lactosylceramide), CD123 (il-3R alpha))or monocyte-related antigens (CD14, CD15). Expression of the mast cell growth factor (MGF) receptor, c-kit(CD117), was also demonstrable, whereas the skin mast cell marker C5aR (CD88) could not be detected on mast cell precursors. The ligand of c-kit, recombinant human (rh) stem cell factor (SCF = MGF), induced histamine release from circulating mast cell progenitors, whereas rhC5a, a potent skin mast cell-/basophil-agonist, was ineffective over the dose-range (10(-9) to 10(-7(M)) tested. Analysis of mast cell antigens in malignant mastocytosis or mast cell leukemias may be helpful to establish a diagnosis and to determine the phenotype of the clone.
Leukemia 1996 Jan
PMID:A case of malignant mastocytosis with circulating mast cell precursors: biologic and phenotypic characterization of the malignant clone. 855 22

Ineffective erythropoiesis due to an impaired response to erythropoietin (EPO) is a prominent abnormality in myelodysplastic syndromes (MDS). The growth factor kit ligand (KL) may restore the in vitro erythroid colony-forming response to EPO in a subset of patients. The inability of MDS erythroid progenitors to react properly to EPO and/or KL has not been resolved. We have investigated erythropoietin receptor (EPO-R) and KL receptor (c-kit) expression in 15 cases of MDS by FACS analysis. The percentage of bone marrow cells expressing the EPO-R from patients with MDS were comparable to normal marrow. No apparent correlation was found between the number of MDS cells coexpressing the EPO-R and CD34 and impaired erythroid response. C-kit was expressed in most MDS patients, including those not responding to KL in EPO-induced cultures. In nine MDS cases the different splice variants of the EPO-R were analyzed. MDS cells, like normal marrow, expressed the full length EPO-R. These results show that impaired erythroid response in MDS cannot be explained by a quantitative lack of receptors for EPO or KL and that most likely suppression of erythroid response is caused by defective receptor signalling following ligand binding, representing a functional defect within the receptor itself or at a level downstream of the receptor.
Leukemia 1996 Mar
PMID:Erythropoiesis in myelodysplastic syndrome: expression of receptors for erythropoietin and kit ligand. 864 63

To characterize Kit expressing mouse bone marrow (BM) cells, and to determine their contribution to short- and long-term repopulation of the hemopoietic system of irradiated recipients, we have purified Kit+ BM cells by flow cytometry. A high level of Kit expression was detectable on 1-2% of BM cells after staining with biologically active biotinylated Kit ligand (KL) or with anti-Kit antibodies (ACK-2). Compared to unfractionated BM, the Kit+ fractions were enriched for immature hemopoietic cells, as shown by morphological differentiation, in vitro culture, and spleen colony formation. Enrichment of colony-forming cells was higher in biotin-KL+ than ACK-2+ fractions. Colony-forming cells were not found in the Kit- subsets. To study the hemopoietic repopulation capacity of the Kit+ and Kit- cells, serial dilutions of the sorted fractions were transplanted into irradiated mice, and peripheral blood of these recipients was monitored regularly for the presence of donor-derived cells during a 1 year period. Nucleated blood cell repopulation by male donor cells in female recipients was assessed using a Y-chromosome specific DNA probe; erythroid repopulation by normal donor cells in W/Wv recipients was examined flow cytometrically by measuring the forward light scatter of donor- and host-type erythrocytes. A 25- to 100-fold enrichment of long-term repopulating ability in the sorted Kit+ fractions showed that Kit+ cells are capable of reconstitution of circulating erythrocytes and nucleated blood cells after BM transplantation. Transient repopulation of the red blood cell lineage was observed after transplantation of Kit- cells. Detection of donor-derived nucleated cells 1 year after transplantation showed that Kit+ cells contributed to donor-type repopulation of bone marrow, spleen and thymus. Our data demonstrate that isolation of BM cells on the basis of Kit expression is a useful addition to the methods that are commonly applied in stem cell enrichment protocols.
Leukemia 1996 Nov
PMID:Purification of repopulating hemopoietic cells based on binding of biotinylated Kit ligand. 889 86

We studied the growth of hematopoietic progenitors at different progressive stages of differentiation and focused especially on changes in cell-cycling. Hematopoietic progenitors from 5-fluorouracil (5-FU)-treated mice were separated into three groups on the basis of differentiation, Stages I, II, and III, and have studied their cell-cycling. Primary marrow cells collected from 5-FU-treated mice were categorized as Stage I progenitors. Stages II and III progenitors are early and late progenies of Stage I progenitors, respectively. The rate of growth of hematopoietic progenitors supported by interleukin-3 (IL-3) and steel factor (SF) was estimated by sequential analysis of colony formation and studying replating efficiency of individual colonies. The time required for hematopoietic progenitors to go through the cell-cycle shortened as their stage of differentiation progressed. Similar results were obtained with other growth factor combinations. The analysis of DNA content of cells suggests that shortening of cell-cycling is mainly due to a decrease in the time of G1 phase of the cell-cycle. Our results demonstrate that in early hematopoiesis, the cell-cycling of hematopoietic progenitors accelerates as they differentiate.
Leukemia 1997 Apr
PMID:Stage-specific cell-cycling of hematopoietic progenitor cells. 920 26

The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor. It is expressed by the primitive CD34 positive haemopoietic stem cells and interacts with the Kit ligand for signal transduction. It was reported to be expressed in over 80% of acute myelogenous leukaemia (AML) patients in North America and Japan. We analyzed 20 AML patients for c-kit expression using either Northern blot analysis or flow cytometry with the YB5.B8 anti-c-kit antibodies. Only 6 out of 20 AML patients expressed the c-kit mRNA or protein product. However, a previously unreported abnormal sized 1.7-1.9 kb transcript was detected in the blast cells of 1 AML patient, 1 acute mixed lineage leukaemia patient and 1 chronic myelogenous leukaemia (CML) patient in myeloblastic transformation. Our data suggested that in most Hong Kong Chinese AML patients, leukaemia transformation may have occurred at a c-kit negative stage. Alternatively, the abnormal sized c-kit transcript that was detected in some Chinese myeloid leukaemia patients may represent an aberrant c-kit receptor that plays an important role in leukaemogenesis.
 ...
PMID:Low frequency of c-kit expression and detection of an aberrant Kit message among Hong Kong Chinese myelogenous leukaemia patients. 921 71

The role of insulin (INS), and insulin-like growth factor-I (IGF-I) in the regulation of human erythropoiesis is not completely understood. To address this issue we employed several complementary strategies including: serum free cloning of CD34+ cells, RT-PCR, FACS analysis, and mRNA perturbation with oligodeoxynucleotides (ODN). In a serum-free culture model, both INS and IGF-I enhanced survival of CD34+ cells, but neither of these growth factors stimulated their proliferation. The influence of INS and IGF-I on erythroid colony development was dependent on a combination of growth factors used for stimulating BFU-E growth. When BFU-E growth was optimally stimulated with erythropoietin (EpO) + kit ligand (KL) the large erythroid colonies developed normally even in the absence of INS or IGF-I. However, the addition of both of these growth factors slightly enhanced colony size. On the other hand, if erythroid colonies were stimulated suboptimally with EpO + IL-3 only, INS or IGF-I increased the number of small erythroid bursts by approximately 30%. Both INS and IGF-I activated signal transduction in maturing human erythropoietic cells as determined by phosphorylation of the insulin receptor substrate-2 (IRS-2) protein. We also found by RT-PCR that mRNA coding for INS-R is expressed in FACS sorted CD34+, c-kit-R+ marrow cells, and in cells isolated from BFU-E and CFU-GM colonies. Expression of INS-R protein on these cells was subsequently confirmed by cytofluorometry. In contrast, the receptor for insulin-like growth factor-I (IGF-IR) was not detected on CD34+ cells, and was first easily detectable on more differentiated cells derived from day 6 BFU-E and CFU-GM colonies. We conclude that INS and IGF-I may be survival factors for human CD34+ cells, but are not required during early erythropoiesis. In contrast, both growth factors may play some role at the final stages of erythroid maturation.
Leukemia 1998 Mar
PMID:The role of insulin (INS) and insulin-like growth factor-I (IGF-I) in regulating human erythropoiesis. Studies in vitro under serum-free conditions--comparison to other cytokines and growth factors. 952 32

CRKL is a 39 kDa adapter protein, originally cloned in proximity to the BCR gene on chromosome 22, which has a key regulatory role in hematopoietic cells. CRKL has one SH2 and two SH3 domains, with 60% homology to CRK II. CRKL is a prominent substrate of the BCR/ABL oncoprotein in chronic myelogenous leukemia and binds to both BCR/ABL and c-ABL. CRKL has been shown to be tryosine phosphorylated in response to normal hematopoietic growth factor receptor signaling with ligands such as thrombopoietin, erythropoietin or steel factor. Additionally, CRKL is involved in signaling initiated by crosslinking of beta integrins, and B cell or T cell receptors. Structurally, the amino-terminal SH3 domain of CRKL has been shown to bind proteins such as C3G, SOS, PI3-K, c-ABL or BCR/ABL. The SH2 domain of CRKL can bind to tyrosine phosphorylated proteins such as CBL, HEF1, CAS or paxillin. This review summarizes the current knowledge on the function of this unique adapter protein in normal hematopoietic and leukemic cell signaling.
Leukemia 1998 May
PMID:Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells. 959 59

Myelodysplasia (MDS) is mostly characterized by a normal or increased number of normoblasts in the bone marrow and an impaired in vitro colony formation. In the present study we analyzed whether this might be due to a disconnection between proliferation and differentiation. CD34+/CD36- sorted bone marrow cells of 18 MDS patients were cultured in a clonogenic and suspension culture assay in the presence of erythropoietin (Epo) and mast cell growth factor (MGF). Burst-forming units erythroid (BFU-E, 75 +/- 88/10(4) CD34+ cells, X +/- s.d.) and colony-forming units E (CFU-E) were observed in eight of the 13 cases (62%) with refractory anemia with or without ring sideroblasts (RA and RARS) and one of the five cases with RA with excess of blasts or in transformation (RAEB and RAEB-T). Suspension cultures with CD34+/CD36- sorted cells with Epo plus MGF demonstrated an 8.9 +/- 6.5-fold expansion after 7 days in cases with >10 BFU-E/10(4) CD34+/CD36- cells while cases with <10 BFU-E/10(4) CD34+/CD36- cells demonstrated 1.0 +/- 0.8-fold expansion especially in cases with RAEB/RAEB-T. FACS and morphology analysis after 7 days of suspension culture demonstrated partial differentiation along the erythroid lineage in cases with RA/RARS (75%) and RAEB/RAEB-T (66%) reflected by the presence of erythroblasts and normoblasts with variable expression of CD34, CD36 and Glycophorin A. In cases with erythroid colony formation 69 +/- 24% of the cells were CD34-/CD36+ and in cases with <10 BFU-E/10(4) CD34+ cells 18 +/- 16% of cells were CD34-/CD36+. Iron staining showed the presence of ring sideroblasts in two cases with RARS indicating that the cells originate from the abnormal erythroid clone. Finally, it was shown that cases with an impaired proliferative response demonstrate an enhanced binding of Annexin-V on CD34+ cells during the first days of the cell suspension culture phase. These results suggest that a defect in the proliferative response is most pronouncedly expressed in MDS whereas a subpopulation of cells retain the capacity to differentiate between transition to a terminated stage.
Leukemia 1998 Jun
PMID:CD34+/CD36- cells from myelodysplasia patients have a limited capacity to proliferate but can differentiate in response to Epo and MGF stimulation. 1008 48

Amifostine (WR-2721, Ethyol) is a phosphorylated aminothiol that affords broad cytoprotection from the myelosuppressive effects of antineoplastics. To further characterize its hematopoietic activities, we investigated the effects of amifostine and its dephosphorylated metabolite, WR1065, on the in vitro growth of human bone marrow progenitors. Preincubation exposure to amifostine or WR1065 stimulated the growth of colony-forming units granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM) and erythroid bursts (BFU-E) from bone marrow mononuclear cells in a dose-dependent fashion. Over the concentration range tested (0.1-1000 microM), pretreatment with the aminothiols enhanced formation of CFU-GEMM up to five-fold and BFU-E nine-fold, compared to a three-fold increase in myeloid colony recovery. In CD34+ selected cells, preincubation with amifostine increased formation of CFU-GEMM up to 38-fold and produced macroscopic colonies, exceeding colony number in cultures initiated with optimal concentrations of interleukin-1 (IL-1), IL-3, or kit ligand (KL). When compared with recombinant human cytokines, amifostine enhanced IL-1 and IL-3 induced colony formation, although its stimulatory effect was less than additive. In contrast, pretreatment with amifostine antagonized the stimulatory effects of KL, whereas synergy was observed with concurrent exposure. Ex vivo expansion studies showed that amifostine alone supported and augmented the production of myeloid progenitors in secondary cultures. Similarly, under cytokine-deficient conditions, amifostine promoted cell survival and delayed apoptosis as measured by nucleosome generation. These data indicate that amifostine is a novel multipotent hematopoietic stimulant that augments the formation and survival of bone marrow progenitors.
Leukemia 1998 Oct
PMID:Amifostine stimulates formation of multipotent and erythroid bone marrow progenitors. 976 5

Flt-3 ligand (FL) is a growth factor (GF) which might have clinical use as a mobilizer of stem and progenitor cells into peripheral blood (PB) in autologous transplantations of various malignant haematological diseases, unless FL stimulates the growth of malignant cells in these diseases. The present study evaluated the effects of FL on the proliferation of granulocytemacrophage (GM) progenitor cells collected from PB of 24 patients with chronic myeloproliferative disorders (MPDs) by using a methylcellulose assay in serum-free culture conditions. It was shown that FL as a single factor had no stimulatory effect on GM colony formation either in the whole MPD group or in the MPD subgroups, which comprised 9 patients with essential thrombocythaemia, 7 with polycythaemia vera and 8 with chronic myelogenous leukaemia. No increase in GM colony formation was observed, either, when FL was used in combination with other GFs, such as mast cell growth factor (MGF), granulocyte-colony stimulating factor (G-CSF), GM-CSF or interleukin-3 (IL-3). GM-CSF and IL-3 were the only single GFs which significantly increased GM colony formation in the whole MPD group. As a conclusion, FL does not seem to induce GM colony formation of MPDs alone or in combination with G-CSF in in vitro colony assays.
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PMID:Flt-3 ligand does not induce the growth of peripheral blood granulocyte-macrophage colony-forming cells in myeloproliferative disorders. 1005 13


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