Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stem cell tyrosine kinase 1 (STK1) protein is the human homologue of the murine FLT3 gene product, a receptor belonging to the FMS/KIT family. FLT3 and KIT with their ligands control the growth and differentiation of early human hemopoietic cells. In the present study, 16 cases of acute myeloid leukemia (AML) were examined by flow cytometry for cell surface expression of FLT3 and KIT receptors. All cases were also tested for their proliferative response to human FLT3 ligand (FL) and KIT ligand (KL) and for colony formation in the presence of single or associated cytokines. Among 16 AML cases tested, 10/16 expressed FLT3 receptor and 12/16 expressed KIT receptor, without any correlation with FAB subtype. FL and KL stimulated the proliferation of leukemic blasts in 11/16 AML cases (including five FLT3 or KIT receptor-negative cases), with an additive effect when added simultaneously. By contrast, some receptor-expressing AMLs did not display significant proliferative responses to their respective ligands. FL and KL as single factors induced or significantly increased the colony formation by clonogenic precursor cells respectively in eight and six of 13 cases tested. In some cases growth factor association significantly enhanced colony growth. Taken together these observations provide evidence that the pattern of FLT3 and KIT receptor expression is extremely variable among the AMLs and that receptor presence is not necessarily combined with proliferative and clonogenic response or vice versa.
Leukemia 1996 Oct
PMID:Expression of type III receptor tyrosine kinases FLT3 and KIT and responses to their ligands by acute myeloid leukemia blasts. 884 93

Interleukin-5 (IL-5), IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) exhibit similar functions on eosinophils, and these common functions are believed to be mediated by the shared beta chain of receptors. IL-5 shows activity on the murine chronic B cell leukemia cell line BCL1-B20, inducing differentiation into IgM-secreting cells, but IL-3 and GM-CSF do not have such activity. To elucidate whether the lineage specificity of IL-5 is due to restricted expression of the IL-5 receptor alpha chain (IL-5R alpha), transfectants of BCL1-B20 were established that express IL-3 receptor alpha (BCL1-3R) or GM-CSF receptor alpha (BCL1-GMR). BCL1-3R and BCL1-GMR acquired responsiveness to IL-3 and GM-CSF, respectively, to an extent similar to IL-5 stimulation, resulting in IgM-secreting cells. Thus, the differentiation of BCL1-B20 into IgM-secreting cells can be equally supported by either IL-3 or GM-CSF, suggesting that intracellular signaling through IL-5R can be replaced by signaling from IL-3R and GM-CSFR. These results support the notion that the lineage specificity of IL-5 is mainly due to the restricted expression of IL-5R alpha. Regulation of IL-5R alpha, IL-3R alpha and GM-CSFR alpha expression in the developmental stage appears to be important for understanding the unique function of these cytokines on a particular cell type.
 ...
PMID:Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce differentiation of chronic B cell leukemia expressing the alpha subunit of IL-3 and GM-CSF receptor. 890 4

Granulocyte-colony stimulating factor (G-CSF) is known to induce proliferation and differentiation of granulocyte progenitors, and is widely used to treat neutropenia induced by intensive chemotherapy for malignant lymphoma or adult T-cell leukaemia/lymphoma (ATL). G-CSF is thought not to stimulate malignant lymphoid cells. In the present study we examined the ability of G-CSF to induce in vitro growth of primary ATL cells from 14 patients (nine acute-type, two chronic-type and three lymphoma-type), and we analysed the in vivo counts of ATL cells in patients who received G-CSF for neutropenia. FACS analysis using phycoerythrin-labelled recombinant G-CSF demonstrated that ATL cells from 11/14 patients express some G-CSF receptor (G-CSFR), with a range between 5.4% and 87.3%. Cells expressing G-CSFR also expressed CD4. Reverse polymerase chain reaction (PCR) analysis demonstrated expression of G-CSFR messenger RNA in G-CSFR expressing cells. Leukaemic cells derived from seven (four acute-type, one chronic-type and two lymphoma-type) of the 14 patients proliferated in vitro in response to G-CSF, as measured by [3H]thymidine incorporation; maximum responses were at G-CSF concentrations of 10-100 ng/ml. Nine of 14 patients receiving rG-CSF for neutropenia were analysed retrospectively for ATL cell numbers. Four patients whose primary tumour cells proliferated in response to rG-CSF in vitro showed a significant increase in ATL cell count after administration of rG-CSF (P = 0.038), whereas five patients whose leukaemic cells did not proliferate in vitro showed no significant increase in ATL cell count. G-CSF can stimulate proliferation of ATL cells which may complicate therapy for this disease.
 ...
PMID:Granulocyte-colony stimulating factor-induced proliferation of primary adult T-cell leukaemia cells. 907 11

Interstitial deletion of chromosome 5q is a common cytogenetic abnormality observed in MDS. We have used fluorescence in situ hybridization (FISH) to determine accurately the percentage of cytogenetically abnormal peripheral blood cells. YAC and cosmid probes localized to chromosome 5q were hybridized to interphase nuclei from purified polymorphonuclear cells (PMNs) from six MDS patients with chromosome 5 deletions. Per patient, 25-67% of the cells exhibited one signal for the 5q31-q33 specific probes IL-4, D5S207 and c-fms. This percentage was constant for the various probes utilized for each patient. Hybridization of the same probes to PMNs from healthy individuals and hybridization of probes (D5S39 and D5S498) localized outside the deleted segments to PMNs of the patients, resulted in 90-95% nuclei with two signals. In addition, FACS-purified peripheral blood cells were investigated by FISH using the IL-4 cosmid. This demonstrated that the hybridization pattern in monocytes was similar to that observed in PMNs, whereas T-lymphocytes showed no loss of signals. These results indicate that a subfraction of the myeloid progenitor cells have acquired the 5q deletion.
Leukemia 1997 Apr
PMID:Mosaicism of the 5q deletion as assessed by interphase FISH is a common phenomenon in MDS and restricted to myeloid cells. 909 92

The SJL/J mouse strain has a high spontaneous incidence of a B-cell neoplasm, reticulum cell neoplasm type B (RCN B). In addition, following irradiation, 10% to 30% of these mice develop acute myelomonocytic leukemia (radiation-induced acute myeloid leukemia [RI-AML]), an incidence that can be increased to 50% by treatment of the mice with corticosteroids after irradiation. The role played by the mononuclear phagocyte growth factor, colony-stimulating factor-1 (CSF-1), in the development of RI-AML in SJL/J mice was investigated. Mice dying of RI-AML, but not those dying of RCN B or without disease, possessed elevated concentrations of circulating CSF-1. In addition, in mice developing RI-AML with a more prolonged latency, circulating CSF-1 concentrations were increased before overt expression of RI-AML. First-passage tumors from 14 different RI-AMLs all contained high concentrations of CSF-1, and six of six different first- or second-passage tumors expressed the CSF-1 receptor (CSF-1 R). Furthermore, in vitro colony formation by first- or second-passage tumor cells from 20 of 20 different RI-AMLs was blocked by neutralizing anti-CSF-1 antibody, and four of four of these tumors were inhibited by anti-CSF-1R antibody. The results of these antibody neutralization studies, coupled with the observation of elevated circulating CSF-1 in mice developing RI-AML, show an autocrine role for CSF-1 in RI-AML development in SJL/J mice. Southern blot analysis of tumor DNA from six of six of these tumors failed to reveal any rearrangements in the genes for CSF-1 or the CSF-1R. Studies in humans have shown that patients with AML possess elevated levels of circulating CSF-1 and that AML cells can express CSF-1 and the CSF-1R. Thus, RI-AML in the SJL/J mouse appears to be a useful model for human AML.
 ...
PMID:Increased circulating colony-stimulating factor-1 (CSF-1) in SJL/J mice with radiation-induced acute myeloid leukemia (AML) is associated with autocrine regulation of AML cells by CSF-1. 911

The possible role of DNA methylation changes during several commitment steps of immature myeloid precursor cells toward functional, terminally differentiated phagocyte cells has previously been examined in the human myeloperoxidase (MPO) and macrophage colony-stimulating factor/c-fms genes using normal and transformed myeloid precursor cells. The human lysozyme (LZM) gene also provides a very useful model, because its protein synthesis is continuously increased during myelopoiesis and thus most abundant in mature phagocytes. Several shifts toward LZM gene demethylation coincide with upregulation of expression: activation of expression in myeloid precursor cells and in primary cells of acute myeloid leukemia (AML) was associated with demethylation at a CpG dinucleotide within the 5' flanking region; high-level expression in different types of normal mature phagocytic cells was associated with complete demethylation at two additional, intragenic CpG sites. Methylation changes occurring within the lysozyme gene could reflect transcriptional control of gene expression or maintenance of distinct maturation stages during phagocyte development. They correlate with maturational arrest and lysozyme gene expression in acute myeloid leukemias and may thus provide a genetic marker for the blocked differentiation of these neoplastic cells. Similar observations have been made for the MPO and c-fms genes.
Leukemia 1997 Mar
PMID:Cytosine methylation changes during normal hematopoiesis and in acute myeloid leukemia. 913 Jun 86

Bryostatin 1 (bryo1), a naturally occurring macrocyclic lactone derived from the marine bryozoan Bugula neritina is a potent protein kinase C (PKC) activator. In this report, we investigated the role of c-fyn protein, a src-related protein tyrosine kinase (PTK), during bryo1-induced monocytic differentiation in a human leukemia cell line, THP-1. Bryo1 treatment for 24 h inhibited the proliferation of THP-1 cells and caused a major fraction of them to become adherent cells with distinct monocyte/macrophage features and enhanced expression of M-CSF receptors (M-CSFR), a hallmark of mature macrophages. The THP-1 cells in control cultures expressed low but detectable levels of c-fyn proteins. Treatment of THP-1 cells with bryo1 resulted in an enhanced expression of c-fyn proteins, but not c-lyn proteins, another member of the src-family of kinases. The bryo1 treatment also enhanced the levels of both c-fyn tyrosine kinase and autophosphorylation activities in THP-1 cells. Using a combined immunoprecipitation and immunoblot analysis, bryo1 was shown to promote an enhanced association between c-fyn kinase and M-CSFR. The inducing activity of bryo1 was associated with PKC activation; treatment of THP-1 cells with bryo1 led to a rapid and transient elevation of total PKC activity in THP-1 cells. These results show that enhanced expression and activation of fyn kinases are critical events associated with monocytic differentiation induced by bryo1 in THP-1 cells. Our findings may be of clinical relevance, as bryo1 has been used in clinical trials of cancer patients.
 ...
PMID:Bryostatin 1 (bryo1)-induced monocytic differentiation in THP-1 human leukemia cells is associated with enhanced c-fyn tyrosine kinase and M-CSF receptors. 922 66

A quantitative analysis of expression levels of GM-CSF receptors was performed by flow cytometry in different disease categories, ie AML (n = 72), ALL (n = 18), and MDS (n = 12), as well as 12 healthy volunteers, using three different unconjugated GM-CSF/R monoclonal antibodies (McAbs) (HGM-CSFR (CD116), M5D12, 4B5F5), and appropriate standards. By using the reference HGM-CSFR McAb, in healthy subjects we found detectable levels of GM-CSF/R on blood monocytes (mean MESF (molecules of equivalent soluble fluorochrome)/cell: 36.1 x 10[3]), neutrophils (mean MESF/cell: 7.4 x 10[3]), bone marrow (BM) myelo-monocytic precursors (MESF range for the myeloid component, ie promyelocytes, myelocytes, metamyelocytes: 11.7-40.5 x 10[3], and for the monocytic lineage: 25.7-69.2 x 10[3]), and in two distinct subsets of BM CD34+ progenitor cells (GM-CSF/R dim: 2.5 x 10[3] MESF/cell, GM-CSF/R bright (10% of the total number of CD34 cells: 22.0 x 10[3] MESF/cell). In these subjects, there was no correlation between the expression levels of GM-CSF/R and CFU (CFU-GM, CFU-GEMM, BFU-E) colony production. Among the AML samples, M5D12 McAb was positive in 33%, 4B5F5 McAb in 90%, and HGM-CSF/R McAb in 78% of the cases examined (range of MESF/cell for the HGM-CSFR McAb: 0.9 x 10[3]-106.7 x 10[3]). The highest MESF values were seen in the M5 FAB subvariety (mean: 39.4 x 10[3]), where all the patients tested (n = 20) showed a strong positivity for the HGM-CSFR McAb. On the contrary, all ALL samples were GM-CSF/R negative except in two patients, who displayed a dim GM-CSF/R positivity (My+ALL: 1.3 x 10[3] MESF/cell; pro-B ALL: 1.0 x 10[3] MESF/cell). In most (>70%) M1 FAB subtypes, GM-CSF/R+ blasts co-expressed CD34low, HLA-DRhigh, CD33, CD38 antigens, and had little or no capacity to form CFU-GM colonies. GM-CSF/R+ blasts from the M5 FAB category were also positive for CD14, CD11c, CD33 and CD87. Furthermore, the number of GM-CSF/R expressed by leukemic cells from five out of 72 (7%) AML patients was above the highest values seen in normal samples (>69.2 x 10[3] MESF/cell), allowing the possibility of using this marker for the monitoring of the minimal residual disease (MRD) in a subset of AML. Cell culture studies aimed at evaluating GM-CSF receptor modulation following AML blast exposure to rhGM-CSF showed two distinct patterns of response; in the first group (6/10 cases) rhGM-CSF down-modulated GM-CSF receptors, whereas in the second group (4/10 cases), rhGM-CSF treatment was associated with either an increase or no change in the number of GM-CSF/R. In conclusion, cellular GM-CSF/R expression was variable and ranged from undetectable (ALL and a minority of AML) to very high intensities in M5 AML, and were also documented in some M0 AML, thus suggesting the concept that GM-CSF/R detection may be of help in lineage assignment of undifferentiated forms. Since the number of GM-CSF/R on AML blasts may be modulated after GM-CSF treatment, it can be postulated that the clinical use of GM-CSF in this disease may be optimized by a dynamic analysis of the number and the affinity status of GM-CSF-R in blasts and normal hemopoietic cells.
Leukemia 1997 Oct
PMID:Flow cytometry measurement of GM-CSF receptors in acute leukemic blasts, and normal hemopoietic cells. 932 92

The Wilms' tumor gene, WT1, encodes a transcription factor of the Cys2-His2 zinc finger type. The functional significance of WT1 expression in leukemias, in addition to tissues and cell lines of hematopoietic origin, has not been determined. Using the murine myeloblastic leukemia cell line M1 as a model for macrophage differentiation, expression of WT1 is shown to be activated in M1 cells 24 hours after differentiation induction by leukemia inhibitory factor (LIF). Upregulation of WT1 in these cells is associated with cellular differentiation, coinciding with expression of the monocyte/macrophage marker c-fms, and the appearance of mature cells. WT1 isoforms lacking the KTS insert are unable to be ectopically expressed in M1 cells. Stable expression of the WT1 isoforms containing the KTS insert leads to spontaneous differentiation of the M1 myeloblasts through the monocytic differentiation pathway. These cells express c-fms, in addition to the myeloid-specific cell surface marker Mac-1. Exposure of these cells to LIF results in the rapid onset of terminal macrophage differentiation, accompanied by apoptotic cell death. These results show that the WT1 gene is an important regulator of M1 cell monocytic differentiation in vitro, and suggests a potential role for this gene in the molecular control of hematopoiesis.
 ...
PMID:Expression of the Wilms' tumor suppressor gene, WT1, is upregulated by leukemia inhibitory factor and induces monocytic differentiation in M1 leukemic cells. 944 34

We previously have exposed U-937 human leukemia cells to stepwise increased concentrations of the anticancer drug etoposide, and this treatment has resulted in stable sublines (termed U-937/RE) exhibiting various extents of resistance to the drug and constitutively expressing c-fms mRNA, a specific marker of monocytic differentiation. In this report, we pursued studies to show that the P-glycoprotein blocker, verapamil, partially restores sensitivity to etoposide in U-937/RE cells. Further, the U-937/RE cells exhibit differential sensitivities to compounds that induce maturation of U-937 cells, as judged by the ability to reduce nitroblue tetrazolium and by morphologic changes, and increased sensitivities to apoptosis induction by the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) and the anticancer drugs 9-nitrocamptothecin and doxorubicin. In addition, the U-937/RE cells, xenografted in immunodeficient mice, demonstrate decreased or no ability to induce tumors. Taken together, these findings indicate that U-937/RE cells differ from the parental U-937 cells in several functional properties and can serve as models to develop protocols for treatment of human leukemia.
 ...
PMID:Altered sensitivities to anticancer and differentiation agents in etoposide-resistant human myeloid leukemia U-937 cells. 950 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>