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

L1210 leukemia cells transport reduced folates and methotrexate via a well defined reduced folate carrier system and, in the absence of low folate selective pressure, do not express an alternate endocytotic route mediated by cell surface folate receptors. This laboratory previously described an L1210 leukemia cell line, MTXrA, with acquired resistance to methotrexate (MTX) due to the loss of mobility of the reduced folate carrier. We now report on the transfection of MTXrA with a cDNA encoding the murine homolog of the human folate receptor isoform of KB cells to produce MTXrA-TF1, which constitutively expresses high levels of FR-alpha. MTXrA-TF1 and L1210 cells were utilized to compare transport of methotrexate mediated by FR-alpha and the reduced folate carrier, respectively. Methotrexate influx in the two lines was similar when the extracellular level was 0.1 microM, but as the methotrexate concentration increased, influx via the reduced folate carrier increased in comparison to influx mediated by FR-alpha. Transport kinetics indicated both a approximately 20-fold lower influx Kb and Vmax for MTXrA-TF1 as compared to L1210 cells. The two cell lines exhibited distinct influx properties. Methotrexate influx in MTXrA-TF1 was markedly inhibited by 50 nM folic acid and metabolic poisons. In L1210 cells, 1.0 microM folic acid did not affect MTX influx, and metabolic poisons either had no effect on or increased methotrexate influx. Removal of extracellular chloride markedly inhibited transport in MTXrA-TF1 but stimulated influx in L1210 cells. When the pH was decreased to 6.2, methotrexate influx was not altered in MTXrA-TF1 but was reduced in L1210 cells. Probenecid and sulfobromophthalein inhibit methotrexate influx in both L1210 and MTXrA-TF1 cell lines; however, inhibition in MTXrA-TF1 could be accounted for on the basis of inhibition of methotrexate binding to FR-alpha. The data indicate that the reduced folate carrier and FR-alpha function independently and exhibit distinct properties. FR-alpha expressed at sufficient levels can mediate influx of MTX and folates into cells at rates comparable to the reduced folate carrier and hence has pharmacologic and physiologic importance.
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PMID:Distinguishing between folate receptor-alpha-mediated transport and reduced folate carrier-mediated transport in L1210 leukemia cells. 771 75

In a panel of acute myeloblastic leukemia (AML) cell lines, representative of distinct differentiation stages, we investigated the possible correlation between drug-resistance and both expression and function of the multidrug resistance (MDR)-related P-glycoprotein (P-gp). The AML cell lines were KG1a, KG1, TF1, HEL, ML1, and two non drug-selected P-gp positive subclones originating from HL-60 (HL-60JD) and U937 (U937AQ). All these cells overexpressed the mdr1 gene (analyzed by RT-PCR) and displayed variable levels of P-gp expression. Flow cytometric semi-quantitative evaluation of P-gp with two P-gp specific monoclonal antibodies (MRK16 and UIC2) showed the following P-gp expression hierarchy: TF1 < KG1a < HEL < KG1 < HL-60JD < ML1 < U937AQ; the latter expressing 13 times more P-gp than TF1. When P-gp function was assessed by Rhodamine 123 (Rh123) efflux kinetics, we found that only KG1a and KG1 cells, which have an early (immature) CD34+ CD33- CD38- phenotype, and to a lesser extent TF1, with an intermediate (CD34+ CD33+ CD38+) phenotype, displayed significant P-gp activity which could be inhibited by both verapamil and SDZ PSC 833. In contrast, the other more mature CD33+ CD34- AML cell lines presented no Rh123 efflux capacity although they expressed higher P-gp levels. Daunorubicin (DNR) accumulation studies showed that inhibitors of P-gp increased DNR accumulation only in the immature AML cells whereas they had no impact on the mature AML cell lines. MTT drug cytotoxicity assay confirmed that the immature AML cells were 10-15-fold more resistant to DNR than the mature AML cells. Although P-gp inhibitors were able to increase the cytotoxicity of DNR in AML cells which displayed functional P-gp, they could not increase DNR cytotoxicity to levels comparable to that of the CD34- CD33+ cells, suggesting that DNR resistance of immature AML cells may not solely be related to P-gp. With drug-selection, AML subclones displayed higher levels of P-gp expression and higher extruding capacities, and therefore chemoresistance, and this independently of their initial differentiation phenotype. Finally, this study provides evidence for a lack of correlation between expression and function of P-gp in AML cells; this relationship being dependent upon leukemic cell differentiation in unselected myeloid leukemic cells.
Leukemia 1995 May
PMID:Lack of correlation between expression and function of P-glycoprotein in acute myeloid leukemia cell lines. 776 42

In 43 patients with leukemia, we determined the increase of tissue factor (TF) activity production by leukemic cells that was induced by incubation with endotoxin at the time of admission. Definite disseminated intravascular coagulation (DIC) developed in 8 patients on admission (Group III) and in 8 patients just after the initiation of treatment (Group II), but not in the remaining 27 patients (Group I). TF activity before incubation (TF1) was 0.70 U/10(8) cells or more in 6 patients of Group III, while it was less in all the patients of Group II and 25 of the 27 patients of Group I. On the other hand, TF activity after incubation with endotoxin (TF2) increased to more than 1.11 U/10(8) cells in all the patients of Groups II and III, while it remained less in all the patients of Group I. These results suggest that the leukemic cells in Group II might not have expressed sufficient TF activity to cause DIC until chemotherapy was begun, and that 1.11 U/10(8) cells or more of TF2 might strongly indicate the development of DIC during treatment for leukemia.
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PMID:Prediction of disseminated intravascular coagulation in patients with leukemia. 806 87

A granulocyte/macrophage colony-stimulating factor (GM-CSF)-Pseudomonas exotoxin (PE) 40 fusion protein was constructed for potential use in the treatment of myeloid leukaemias, as a conditioning agent prior to allogeneic bone marrow transplantation or for ex vivo purging of malignant cells prior to autologous bone marrow transplantation. The GM-CSF-PE40 fusion protein successfully binds to the GM-CSF receptor and is capable of initiating a mitogenic signal similar to native GM-CSF in the GM-CSF-dependent TF1 cell line. The toxin component also appears to be fully functional as determined by an in vitro adenosine diphosphate-ribosylation assay. The GM-CSF-PE40 fusion protein, however, was not cytotoxic to a number of myeloid leukaemia cell lines. It is suggested that the mechanism of internalization of the GM-CSF receptor is not appropriate for the translocation of PE to the cytosol where it can fulfil its cytotoxic potential.
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PMID:A recombinant GM-CSF-PE40 ligand toxin is functionally active but not cytotoxic to cells. 924 95

We studied the expression of the mineralocorticoid receptor (MCR), and of the amiloride-sensitive sodium channel (ASSC) regulated by the MCR, in human leukemic cell lines. Cell extracts from TF1 (proerythroblastic), HEL (human erythroblastic leukemia) and U937 (myeloblastic) cell line were positive for the ASSC, as a 82 kDa band in Western blots developed with the aid of a polyclonal antibody raised against the peptide QGLGKGDKREEQGL, corresponding to the region 44-58 of the alpha subunit of the epithelial sodium channel (ENaC) cloned from rat colon, linked to KLH. The polyclonal antibody against the MCR revealed a single band of about 102 kDa in extracts from HEL and TF1 cells. The immunofluorescent labelling of the MCR in all cell lines showed a nucleocytoplasmic localization of the receptor but the ASSC was exclusively membrane-bound and these results were confirmed by confocal microscopy. The expression of the MCR in the HEL cells was evident as a predicted band of 843 bp (234 amino acids) in electrophoresis of the PCR product obtained after total RNA had been reverse transcribed and then amplified using the primers 5'-AGGCTACCACAGTCTCCCTG-3' and 5'-GCAGTGTAAAATCTCCAGTC-3' (sense and antisense, respectively). The ENaC was similarly evident with the aid of the primers 5'-CTGCCmATG GATGATGGT-3' (sense) and 5'-GTTCAGCTCGAAGAAGA-3' (antisense) as a predicted band of 520 bp. In both cases, 100% identity was observed between the sequences of the PCR products compared to those from known human sources. The multiplication of the HEL cells was influenced by antagonists (RU 26752, ZK 91587) targeted for specificity to the MCR and this was selectively reversed by the natural hormone aldosterone. These steroids also provoked chromatin condensation in the HEL population. These permit new and novel possibilities to understand the pathobiology of human leukemia and to delineate sodium-water homeostasis in nonepithelial cells.
Leukemia 2000 Jun
PMID:Demonstration of the mineralocorticoid hormone receptor and action in human leukemic cell lines. 1086 75

The expression of LeY, H2, H3, and H4 on a broad variety of human leukemia cell lines and native lymphocytes as well as on CD34+ hematopoietic progenitor cells was examined by flow cytometry and immunocytochemistry. CD34+ leukemia cell lines (KG1, KG1a, and TF1) and native CD34+ hematopoietic progenitor cells expressed H2 (CD173) and LeY (CD174). In contrast, CD34(-) cell lines (HL-60, U937, JOK-1, Raji, Molt-3, Jurkat, and CEM-C7) and mature lymphocytes from peripheral blood and tonsils lacked CD173 and CD174. All cell lines and native lymphocytes as well as CD34+ precursor cells were negative for H3 and H4. Immunoprecipitation and consecutive Western blotting revealed a 170-kDa glycoprotein as the carrier molecule for the CD173 and CD174 oligosaccharide sequences on CD34+ hematopoietic precursors. The key enzyme for generating CD173 is the beta-D-galactoside 2-alpha-L-fucosyltransferase (FUT1). As shown by RT-PCR, FUT1 was expressed in immature hematopoietic cells but absent in mature lymphocytes, which indicates that expression of CD173 within the hematopoietic system is regulated at the transcriptional level by FUT1. Due to their exclusive presence on CD34+ hematopoietic progenitor cells, CD173 and CD174 represent novel markers of early hematopoiesis. The expression of the fucosylated histo-blood group antigens CD173 and CD174 in CD34+ hematopoietic progenitor cells and down-regulation of FUT1 in mature lymphocytes may be important factors influencing the homing process of hematopoietic stem cells to the bone marrow.
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PMID:The fucosylated histo-blood group antigens H type 2 (blood group O, CD173) and Lewis Y (CD174) are expressed on CD34+ hematopoietic progenitors but absent on mature lymphocytes. 1147 78

The novel fusion protein DT(388)IL3, composed of the catalytic and translocation domains of diphtheria toxin (DT(388)) fused with a Met-His linker to human interleukin 3 (IL-3), was tested for anti-leukemia efficacy in an in vivo model of differentiated human acute myeloid leukemia (AML). Six-week-old female SCID mice were irradiated with 350 cGy, inoculated 24 h later with 20 million (i.v., i.p., or s.c.) TF1 cells transfected with the v-SRC oncogene, and treated i.p., starting 24 h later, with up to five daily injections of saline, DT(388)IL3 (2 microg), DT(388)GMCSF (2 microg), DAB(389)IL2 (2 microg), or cytarabine (80 microg) or two weekly injections of anti-CD33-calicheamicin conjugate (5 microg). Animals were monitored twice daily, and moribund animals killed and necropsied. Control animals had a median disease-free survival (DFS) of 37 days (i.v., n = 45), 35 days (i.p., n = 20), and 21 days (s.c., n = 20), respectively. Only 5/49 (10%) of the DT(388)IL3 treated i.v. inoculated animals died with leukemia. Median DFS with i.v., i.p. and s.c. tumor inoculated animals was prolonged by fusion protein treatment to >120 days, 66 days and 31 days (P < 0.001, = 0.0003, and = 0.0006), respectively. Median DFS with s.c. tumor inoculated animals was also prolonged by other active anti-leukemia agents (DT(388)GMCSF, cytarabine and anti-CD33-calicheamicin) relative to controls by 67%, 172% and 47% (P < 0.0001, <0.0001, and =0.0004), respectively. In contrast, median DFS with s.c. tumor inoculated animals treated with DAB(389)IL2 non-significantly reduced by 13% relative to controls (P = 0.21). Thus, DT(388)IL3 fusion protein demonstrates in vivo anti-leukemia efficacy and warrants further preclinical development for treatment of chemo-resistant, IL-3 receptor positive AML patients.
Leukemia 2003 Jan
PMID:Diphtheria toxin-interleukin-3 fusion protein (DT(388)IL3) prolongs disease-free survival of leukemic immunocompromised mice. 1252 73

An inevitable trend for the development of new treatment of leukemia is to use targeted strategy. IL-6/IL-6R is important one of the cytokine receptor targeted treatment systems. Many malignant cells, including multiple myeloma, prostate carcinoma and leukemia etc., have been shown to express IL-6R. Leukemia cells, especialy in U937, TF1, KG1 cell lines highly express the high affinity IL-6R. IL-6 recombinant toxin is cytotoxic in vitro to leukemia cell expressing high affinity IL-6R; in vivo the fusion toxin can result the reduction of leukemic cell load in animal leukemia model but have no effect on normal hematopoiesis in non-leukemic animal. On the basis of these pre-clinical studies, IL-6 recombinant toxin my become novel drug for the treatment of leukemia and cancer in future.
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PMID:[A Strategy of IL-6/IL-6R System Mediates Targeted Treatment for Leukemia] 1257 31

Survival and proliferation of cells of a human myelo-erythroid CD34+ leukemia cell line (TF-1) depend on the presence of granulocyte-macrophage colony-stimulating factor or interleukin-3. Upon hormone withdrawal these cells stop proliferating and undergo apoptotic process. In this report we demonstrate that a controlled increase in [Ca2+]i induces hormone-independent survival and proliferation of TF-1 cells. We found that moderate elevation of [Ca2+]i by the addition of cyclopiasonic-acid protected TF1 cells from apoptosis. Furthermore, a higher, but transient elevation of [Ca2+]i by ionomycin treatment induced cell proliferation. In both cases caspase-3 activity was reduced, and Bcl-2 was up-regulated. Higher elevation of [Ca2+]i by ionomycin induced MEK-dependent biphasic ERK1/2 activation, sufficient to move the cells from G0/G1 to S/M phases. Meanwhile, activation of ERK1/2, phosphorylation of the Elk-1 transcription factor, and, consequently, a substantial elevation of Egr-1 and c-Fos levels and AP-1 DNA binding were observed. Moderate elevation of [Ca2+]i, on the other hand, caused a delayed monophasic activation of ERK1/2 and Elk-1 that was accompanied with only a small increase of Egr-1 and c-Fos levels and AP-1 DNA binding. The specific MEK-1 kinase inhibitor, PD98059, inhibited all the effects of increasing [Ca2+]i, indicating that the MAPK/ERK pathway activation is essential for TF-1 cell survival and proliferation. Based on these results we suggest that the elevation of the [Ca2+]i may influence the cytokine dependence of hemopoietic progenitors and may contribute to pathological hematopoiesis.
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PMID:Calcium induces cell survival and proliferation through the activation of the MAPK pathway in a human hormone-dependent leukemia cell line, TF-1. 1264 64

NALP1 (also called DEFCAP, NAC, CARD7) has been shown to play a central role in the activation of inflammatory caspases and processing of pro-IL1b (pro-interleukin-1b). Previous studies showed that NALP1 is highly expressed in peripheral blood mononuclear cells. In the present study, we report that expression of NALP1 is absent from CD34+ haematopoietic blast cells, and its levels are upregulated upon differentiation of CD34+ cells into granulocytes and to a lesser extent into monocytes. In peripheral blood cells, the highest levels of NALP1 were observed in CD3+ (T-lymphocytes), CD15+ (granulocytes) and CD14+ (monocytes) cell populations. Notably, the expression of NALP1 was significantly increased in the bone marrow blast cell population of some patients with acute leukaemia, but not among tissue samples from thyroid and renal cancer. A search for consensus sites within the NALP1 promoter revealed a sequence for CREB (cAMP-response-element-binding protein) that was required for transcriptional activity. Moreover, treatment of TF1 myeloid leukaemia cells with protein kinase C and protein kinase A activators induced CREB phosphorylation and upregulated the mRNA and protein levels of NALP1. Conversely, ectopic expression of a dominant negative form of CREB in TF1 cells blocked the transcriptional activity of the NALP1 promoter and significantly reduced the expression of NALP1. Thus NALP1 is transcriptionally regulated by CREB in myeloid cells, a mechanism that may contribute to modulate the response of these cells to pro-inflammatory stimuli.
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PMID:NALP1 is a transcriptional target for cAMP-response-element-binding protein (CREB) in myeloid leukaemia cells. 1528 19


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