Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multidrug resistance-associated protein (MRP) gene is a member of the ATP-binding cassette transporter gene superfamily and may be partially responsible for clinical drug resistance. Reverse transcriptase-polymerase chain reaction was used to measure MRP mRNA in normal hematopoietic cells from bone marrow and peripheral blood as well as patients with high risk acute myelocytic leukemia and multiple myeloma. All normal peripheral blood cells, regardless of cell lineage (CD4, CD8, CD14, CD15, CD19, CD56), expressed a similar basal level of MRP mRNA. Specimens from bone marrow containing mixed lineages also expressed a similar basal level of MRP expression. In patients with acute myelocytic leukemia, 10 of 12 (83%) of the specimens had detectable MRP mRNA, but the level of expression was similar to that of normal blood cells and low compared to a cell line known to overexpress MRP (H69/AR). All myeloma patients (12 of 12) had detectable MRP mRNA expression at levels comparable to normal peripheral blood and bone marrow cells. We conclude that MRP is commonly expressed in normal hematopoietic cells as well as certain hematopoietic malignancies. The therapeutic relevance of MRP expression is unknown, but these studies emphasize the importance of measuring MRP expression in normal cells as a point of reference and comparison for detection in malignant cells. We also recommend obtaining sequential specimens from patients, which may reveal an increased expression of MRP from baseline as the disease progresses and becomes resistant.
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PMID:Analysis of multidrug resistance-associated protein (MRP) messenger RNA in normal and malignant hematopoietic cells. 806 63

Remission marrow from patients with BCR-ABL+ acute lymphoblastic leukemia (ALL) achieving clinical remission (CR) after induction or consolidation chemotherapy according to the German multicenter adult ALL (GMALL) protocol showed high titers of residual BCR-ABL+ cells. Therefore, we initiated a pilot study to monitor circulating BCR-ABL+ cells and to collect, purge, and autograft peripheral blood stem cells (PBSC) in these patients. After GMALL 05/93 high-risk phase II of induction chemotherapy (high-dose AraC 3 g/m2 x 8 does and mitoxantrone 10 mg/m2 x 3 doses), patients received 5-10 micrograms/kg subcutaneous recombinant human granulocyte colony-stimulating factor (rhG-CSF) daily. Mobilized CD34+ cells peaked between 20 and 26 days after starting chemotherapy at 4.8-75.6 (median 10.8) x 10(4)/mL peripheral blood (PB) (n = 5). Patients treated with additional chemotherapy cycles failed to mobilize adequate numbers of CD34+ cells. PB stem cells (PBSC) were purged using a cocktail of CD10, CD19, and AB4 monoclonal antibodies (mAbs) coupled to immunomagnetic beads (IMB). The median recoveries of total nucleated cells (TNC) and CD34+ cells after mAb/IMB purging were 84 and 81%. The peak numbers of CD34+ cells collected in a single leukapheresis were median 8.6 x 10(6)/kg pre- and 5.2 x 10(6)/kg postpurge (n = 4). The absolute prepurge CD19+ cells were as low as median 2.7 (range 1.4-19) x 10(6) per leukapheresis. Residual BCR-ABL+ cells in unpurged leukapheresis products were assessed by limiting-log10-dilution nested reverse-transcriptase polymerase chain reaction (RT-PCR) as one in 10(5) to one in 10(6) normal cells and were consistently undetectable in all purged PBSC autografts. We conclude that sufficient numbers of CD34+ cells for PBSCT can be collected after phase II but not at later stages of the GMALL 05/93 high risk protocol; PBSC grafts are 3 log less contaminated with residual BCR-ABL+ cells compared to an historical series of 13 autologous BM grafts; and purging of PBSC with mAb/IMB is feasible with minor loss of CD34+ cells and abolished BCR-ABL signals in the grafts.
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PMID:Purging of peripheral blood stem cells yields BCR-ABL-negative autografts in patients with BCR-ABL-positive acute lymphoblastic leukemia. 854 55

We investigated the effects of Flt3/Flk-2 ligand (FL) and interleukin-7 (IL-7) on DNA synthesis and proliferation of blast cells from patients with acute lymphoblastic leukemia (ALL). After 7 days of serum-free suspension culture of 19 samples, FL induced maximal DNA synthesis in two cases, whereas the combination of FL and IL-7 did so in another eight samples with a stimulation index (SI) >2. However, the number of viable cells after 7 days of liquid culture decreased in all but one sample. In this case of a pre-pre-B-ALL with a translocation t(4;11), FL induced dose-dependent proliferation (maximal 100 ng/mL) and cells stimulated with FL could be cultured for up to 4 weeks. A homogeneous population with 98% CD19-positive cells was detected before and after culture, and there was no evidence of nonleukemic cell proliferation as determined by immunophenotyping. The flt3 gene was transcribed in all seven cases studied by reverse-transcriptase polymerase chain reaction (RT-PCR). In the ALL cells responsive to FL, the expression of functional Flt3 receptors was confirmed by demonstrating FL-dependent tyrosine phosphorylation of Flt3. Furthermore, FL-dependent tyrosine phosphorylation of cellular proteins of estimated molecular weights of 70, 115, and 140 kD was detectable in these cells. These data demonstrate the functional heterogeneity of ALL samples and show that functional Flt3 receptors capable of mediating FL-dependent mitogenic signaling are expressed in a subset of ALL.
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PMID:Effects of Flt3 ligand and interleukin-7 on in vitro growth of acute lymphoblastic leukemia cells. 864 68

Reciprocal communication between the immune system and the neuroendocrine system is mediated via a common chemical language of shared ligands and receptors. The neuropeptide substance P (SP) has been implicated as a mediator of immunomodulation. The evidence for substance P receptors on human lymphocytes is, however, controversial. The aims of the present study are to investigate substance P receptor (SPR) expression in human peripheral and mucosal mononuclear cells and to identify cellular sites of expression in human colonic mucosa. Using reverse-transcriptase PCR, we demonstrate that PBMC isolations are negative for SPR mRNA expression, whereas lamina propria mononuclear cell (LPMC) isolations express on average eight SPR mRNA transcripts per cell. In situ hybridization performed on surgically resected colonic tissue confirms the expression of SPR mRNA in LPMC in vivo. SPR mRNA signal was detected in LPMC, lymphoid follicles, and epithelium. The complementary technique of immunohistochemistry gave a similar distribution of SPR expression that colocalized with CD45 immunoreactivity. Dual-fluorochrome flow cytometry revealed SPR expression by CD4, CD45RO, CD45RA, CD8, CD19, and CD14 LPMC subsets, but not PBMC. Our findings suggest that SPR expression is distinctive of human colonic mucosal mononuclear cells and support a direct role for SP in mucosal immunomodulation.
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PMID:Substance P (neurokinin-1) receptor is a marker of human mucosal but not peripheral mononuclear cells: molecular quantitation and localization. 972 16

Theophylline, a drug known to inhibit several classes of adenosine 3'5' cyclic monophosphate (cAMP) phosphodiesterases (PDEs), induces apoptosis in chronic lymphocytic leukemia (CLL) cells. Because the PDE target for theophylline in CLL remains unknown, we examined the ability of isoform-specific PDE inhibitors to increase cAMP levels and induce apoptosis in primary CLL cells. Reverse transcriptase-polymerase chain reaction of purified CLL cDNA amplified transcripts for PDE1B, 4A and 4B. The type 4 PDE inhibitor rolipram but not the type 1 inhibitor vinpocetine increased CLL cAMP levels. Rolipram-inhibitable (type 4) but not calcium-calmodulin augmented (type 1) PDE enzyme activity was detected in CLL samples. In samples from 13 of 14 CLL patients, rolipram induced apoptosis in a dose-dependent fashion over a 48-hour period. Interleukin-2 (IL-2)-cultured whole mononuclear cells (WMC) and anti-Ig stimulated CD19(+) B cells were resistant to the induction of apoptosis by rolipram while unstimulated CD19(+) B cells, which had a high basal apoptotic rate, were more sensitive. Rolipram stimulated elevations in cAMP levels in all four of these cell populations, suggesting that they differed in sensitivity to cAMP-induced apoptosis. Consistent with this hypothesis, incubation with the cell permeable cAMP analog dibutyryl-cAMP induced apoptosis in CLL cells and unstimulated B cells but not in IL-2-cultured WMC or anti-Ig stimulated B cells. These data identify PDE4 as a family of enzymes whose inhibition induces apoptosis in CLL cells.
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PMID:Type 4 cyclic adenosine monophosphate phosphodiesterase as a therapeutic target in chronic lymphocytic leukemia. 974 89

We describe a long-term, in vitro culture system initiated with CD34(+) or CD34(+)CD38(-) umbilical cord blood hematopoietic progenitors that supports normal human B-lineage development, including the production of mature Ig-secreting B cells. In the first stage (human B-progenitor long-term culture [HB-LTC]), CD34(+) hematopoietic progenitors are cultured on the murine stromal cell line, S17, leading to the sustained production of large numbers of CD10(+), CD19(+) early B progenitors. Reverse transcriptase-polymerase chain reaction (RT-PCR) and three-parameter flow cytometry for VpreB (surrogate light chain), cytoplasmic mu chain, and surface IgM expression were used to characterize the CD19(+) B progenitors present within these cultures. This analysis showed distinct B-lineage subpopulations, including pro-B cells, cycling pre-B cells, and IgM+, IgD-/+ immature B cells. The limited expansion of IgM+ B cells and the immature surface phenotype of this population (IgM+, IgD+, CD10(+), CD38(+)) suggested that HB-LTC conditions were unable to provide appropriate signals for further differentiation. A second culture stage was used to determine if these immature B cells were functionally competent. Purified CD19(+) cells were transferred onto fibroblasts expressing human CD40-ligand in the presence of IL-10 and IL-4. This lead to cell proliferation, modulation of the IgM+ cell surface phenotype to one consistent with an activated mature B cell, secretion of Ig, and isotype switching. Notably, IgM and IgG producing B cells were also generated using two-stage cultures established with highly purified multipotent CD34(+)CD38(-) hematopoietic stem cell progenitors. This culture model should permit detailed in vitro analysis and genetic manipulation of the major transition points in human B ontogeny, beginning with commitment to the B lineage and leading to development and activation of mature B cells.
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PMID:In vitro reconstitution of human B-cell ontogeny: from CD34(+) multipotent progenitors to Ig-secreting cells. 984 15

In addition to the Epstein-Barr virus (EBV) EBNA and LMP latency genes, there is a family of alternatively spliced BamHI-A rightward transcripts (BARTs). These latency transcripts are highly expressed in the EBV-associated malignancies nasopharyngeal carcinoma and Burkitt's lymphoma, and are expressed at lower levels in latently EBV-infected B-cell lines. The contribution of the BARTs to EBV biology or pathogenesis is unknown. Resting B cells have recently been recognized as a reservoir for EBV persistence in the peripheral blood. In these cells, EBV gene expression is tightly restricted and the only viral gene known to be consistently expressed is LMP2A. We used cell sorting and reverse-transcriptase polymerase chain reaction (RT-PCR) to examine whether BARTs are expressed in the restricted form of in vivo latency. Our results demonstrated that RNAs with splicing diagnostic for transcripts containing the BART RPMS1 and BARFO open-reading frames (ORFs) were expressed in CD19(+) but not in CD23(+) B cells isolated from peripheral blood of healthy individuals. The product of the proximal RPMS1 ORF has not previously been characterized. The RPMS1 ORF was shown to encode a 15-kD protein that localized to the nucleus of transfected cells. Expression of the BARTs in peripheral blood B cells suggests that the proteins encoded by these transcripts are likely to be important for maintenance of in vivo latency.
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PMID:Expression of Epstein-Barr virus BamHI-A rightward transcripts in latently infected B cells from peripheral blood. 1021 99

This study compared human murine stromal cells for their capacity to support human hematopoietic stem cell (HSC) development into the B lineage. FACS sorted human fetal bone marrow (BM) HSC (CD34+CD19- or CD34+/CD10-/CD19-/CD45RA) were cultured on human fetal BM stromal cells, human skin fibroblasts, or murine S17 stromal cells and analyzed by flow cytometry or reverse transcriptase polymerase chain reaction. CD34+CD19- HSC on human BM stromal cells or fibroblasts differentiated into B-lineage cells with a continuum in density of surface CD19 expression, and some cells expressing micro/kappa or micro/lambda B-cell receptors. In contrast, CD19+ cells from S17 cultures had two- to fourfold higher levels of CD19, but no cells expressing B-cell receptors. The number and percentage of CD19+ cells was high, intermediate, or low in the human BM, human fibroblast, or murine S17 stromal cell cultures, respectively. Reverse transcriptase polymerase chain reaction analysis showed that TdT, CD19, and DHQ52-J(H) rearrangements were expressed at comparable levels when CD34+/CD19- HSC were plated on human or murine stromal cells. In contrast, CD34+/CD10-/CD19-/CD45RA HSC plated on human or murine stromal cells expressed CD19 in both cultures, but TdT was only expressed in human stromal cell cultures. We conclude that human BM stromal cell, human skin fibroblasts, and murine S17 stromal cell cultures can provide complementary and comparative tools for identification of stromal cell ligands with potentially unique functions in regulating human B-cell development.
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PMID:Comparative studies of different stromal cell microenvironments in support of human B-cell development. 1042 4

"Simple" variants of the t(8;21) translocation involving chromosome 8 and a chromosome other than number 21 are rare. To our knowledge, only t(3;8)(q29;q22), t(8;11)(q22;q13), t(8;16)(q22;q24), t(8;20)(q22;p13), and t(8;22) have been reported in the literature. This paper describes for the first time two patients with acute myelogenous leukemia with a consistent t(8;19)(q22;q13) translocation. Their myelograms were compatible with the FAB-M2 subtype. The blasts from case 2 expressed CD34, CD33, CD13, and CD19. Karyotype analyses were performed on bone marrow cells using R- and G-banding at presentation. A t(8;19)(q22;q13) translocation was found in 28/30 metaphases for case 1 and in 23/25 metaphases for case 2. The latter case also had a deletion of chromosome 9, del(9)(q12q22) as an additional abnormality. Reverse transcriptase-polymerase chain reaction study revealed no AML1/ETO fusion transcript in case 2. Dual-color fluorescence in situ hybridization (FISH) assay using two probes (BAC92 and YAC412A4) convincingly demonstrated that the chromosomal material from 8q was translocated onto 19q rather than 19p in case 2. Thus, we consider t(8;19)(q22;q13) a true "simple" variant of t(8;21), and assume that a fusion gene resulting from the t(8;19) may contain the ETO gene located at 8q22 and an unknown partner gene from 19q13, which probably is a new transcription factor, whose molecular entity warrants further study.
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PMID:Two cases of AML (M2) with a t(8;19)(q22;q13): a new cytogenetic variant. 1074 98

CD320 has been recently discovered and reported as a follicular dendritic cell (FDC) protein. Although CD320 is known to enhance proliferation of germinal center (GC) B cells, little other information is available. In this study, we investigated its cellular distribution in the GC. Confocal microscopy of human tonsil sections revealed co-localization of CD320 with CD19 and CD38 but not with CD3 indicating that GC B cells expressed CD320 in addition to FDC. In purified GC B cells, CD320 expression was inhibited in the nucleus, membrane and cytoplasm. Reverse transcriptase-polymerase chain reaction confirmed CD320 mRNA expression in B cells. These finding indicate that CD320 is expressed in B cells in addition to FDC, and that its GC activity may be more complicated than previously thought.
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PMID:Expression of CD320 in human B cells in addition to follicular dendritic cells. 1912 77


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