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

Twenty-five patients with B-cell chronic lymphocytic leukemia (B-CLL) were investigated to correlate the immunological phenotype with the description of the Ig gene rearrangements of the B-cell clone. All patients were positive for the CD19 antigen and one pan B-antigen, markers of late cells (CD20, CD37 or Y2955). Twenty-four of the 25 patients tested expressed monoclonal cell surface immunoglobulin (SIg). The CD5 antigen was present in 21 of the 25 tested patients. Immunoglobulin gene rearrangements were detected by hybridization of the BamHI, EcoRI, BgIII, and HindIII digested genomic DNAs to the IGHJ, IGKC, IGLC, and IGLJ2 probes. Twenty-four of 25 patients had two rearranged IGH loci. The IGKC rearrangements were observed in 20 patients. In four patients, the IGK loci were deleted on both chromosomes. One patient without SIg displayed a germline pattern. All six patients with lambda producing B-CLL showed a lambda gene rearranged band, although the use of IGL polymorphism to investigate IGL rearrangements must be noted. These clonal rearrangements of IGL genes, together with the detection of either the kappa or lambda light chain of SIg, confirm that patients with B-CLL meet the developmental scheme of ordered light chain gene rearrangements.
Leukemia 1991 Nov
PMID:Rearrangements of immunoglobulin light and heavy chain genes and correlation with phenotypic markers in B-cell chronic lymphocytic leukemia. 196 Oct 33

Translocation t(3;22)(q27;q11) has recently been recognized as a recurrent abnormality in non-Hodgkin's malignant lymphoma (NHL). A new gene, LAZ3, has been shown to be involved in NHL with 3q27 rearrangement. Two patients with B-cell NHL were studied by chromosome painting and Southern blot analysis. Fluorescence in situ hybridization to metaphase chromosomes was shown to be an easy way to detect the chromosomal abnormality even in metaphase cells with poorly defined chromosomes. The gene LAZ3 was rearranged in one patient in the 'major translocation cluster region'. The comigration of rearranged LAZ3 and of IGL bands suggests that the translocation resulted in the juxtaposition of the two genes. This juxtaposition makes possible a potential deregulation of the LAZ3 gene expression, as previously shown for the MYC and BCL2 genes in Burkitt and follicular lymphoma translocations.
Leukemia 1993 Dec
PMID:Translocation t(3;22)(q27;q11) in non-Hodgkin's malignant lymphoma: chromosome painting and molecular studies. 825 95

We investigated the effect of the histone deacetylase inhibitors (HDIs), trichostatin A and trapoxin A on leukemia cells and cell lines from the viewpoint of differentiation induction. TSA induced differentiation in erythroid cell lines by itself, whereas it synergistically enhanced the differentiation that was directed by all-trans retinoic acid (ATRA) or vitamin D3 in U937, HL60 and NB4 cells. The combined treatment of HDI with ATRA induced differentiation in ATRA-resistant HL60 and NB4 cells. The transcriptional expression during the treatment with HDI was examined in HL60, U937 and MEG-O1. Cell cycle-regulator genes (p21waf1 and p16INK4A) were upregulated or constantly expressed, erythroid-specific genes (GATA-1, beta-globin) were silent or downregulated, and housekeeping genes (beta-actin and GAPDH) were constantly expressed. Twelve of 35 (34%) clinical samples from AML patients ranging from M0 to M7 also displayed both phenotypical and morphological changes by the treatment with TSA alone. HDIs are thus the potent inducer or enhancer of differentiation in acute myeloid leukemia and regulate transcription in an ordered manner.
Leukemia 1999 Sep
PMID:Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy. 1048 80

Gene therapy strategies employing the HSVtk/ganciclovir (GCV) suicide gene offer promising approaches towards the treatment of metastatic breast cancer. These include bystander effects on non-transduced tumor cells, lower systemic toxicity, and the possibility of inducing immunity against the tumor. Previously we have demonstrated the ability of the grp78 stress-inducible promoter to stimulate expression of reporter genes within the tumor microenvironment. However, experimental evidence demonstrating the ability of this promoter to activate therapeutic agents within the breast cancer environment causing tumor eradication is needed prior to clinical trials. In this report, we test the efficacy of the grp78 promoter in a retroviral system to drive the expression of the HSVtk suicide gene in a murine mammary adenocarcinoma cell line (TSA) in syngeneic, immune-competent hosts. Our results show that under glucose-starvation conditions in vitro, the expression of HSVtk and GCV induced cell death are enhanced in tumor cells in which the HSVtk gene is driven by the internal grp78 promoter compared to cells in which the Moloney murine leukemia virus LTR drives HSVtk. In in vivo studies, in tumors in which the HSVtk gene is driven by the grp78 promoter, GCV treatment causes complete tumor eradication, whereas tumors persist when the HSVtk gene is driven by the retroviral LTR. Our study suggests that the grp78 promoter may be useful to enhance the effectivity of therapeutic agents within a breast tumor. In addition, it is shown that immune memory is induced in syngeneic, immune-competent hosts. This new retroviral vector might therefore be useful for breast cancer gene therapy.
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PMID:Eradication of murine mammary adenocarcinoma through HSVtk expression directed by the glucose-starvation inducible grp78 promoter. 1075 83

Overexpression of the human multidrug resistance gene 1 (MDR1) is a negative prognostic factor in leukemia. Despite intense efforts to characterize the gene at the molecular level, little is known about the genetic events that switch on gene expression in P-glycoprotein-negative cells. Recent studies have shown that the transcriptional competence of MDR1 is often closely associated with DNA methylation. Chromatin remodeling and modification targeted by the recognition of methylated DNA provide a dominant mechanism for transcriptional repression. Consistent with this epigenetic model, interference with DNA methyltransferase and histone deacetylase activity alone or in combination can reactivate silent genes. In the present study, we used chromatin immunoprecipitation to monitor the molecular events involved in the activation and repression of MDR1. Inhibitors of DNA methyltransferase (5-azacytidine [5aC]) and histone deacetylase (trichostatin A [TSA]) were used to examine gene transcription, promoter methylation status, and the chromatin determinants associated with the MDR1 promoter. We have established that methyl-CpG binding protein 2 (MeCP2) is involved in methylation-dependent silencing of human MDR1 in cells that lack the known transcriptional repressors MBD2 and MBD3. In the repressed state the MDR1 promoter is methylated and assembled into chromatin enriched with MeCP2 and deacetylated histone. TSA induced significant acetylation of histones H3 and H4 but did not activate transcription. 5aC induced DNA demethylation, leading to the release of MeCP2, promoter acetylation, and partial relief of repression. MDR1 expression was significantly increased following combined 5aC and TSA treatments. Inhibition of histone deacetylase is not an overriding mechanism in the reactivation of methylated MDR1. Our results provide us with a clearer understanding of the molecular mechanism necessary for repression of MDR1.
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PMID:Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation. 1186 62

Histone deacetyrase (HDAC) inhibitors induce growth arrest and differentiation of leukemia cell lines and tumor cells derived from a large variety of human tissues. Here we showed that HDAC inhibitors sodium butyrate, TSA, and valproate regulated the expression of Interleukin-18 (IL-18), a cytokine with antitumor and proinflammatory properties, in human acute myeloid leukemia cell lines U937 and HEL. Sodium butyrate increased expression of IL-18 protein and mRNA and activated 1357bp IL-18 gene promoter construct. IL-18 mRNA level was up-regulated by TSA or valproate, which also activated IL-18 full-length promoter. While sodium butyrate or TSA stimulated the 108-bp IL-18 minimal promoter, valproate failed to activate it, indicating that valproate may use a distinct mechanism from sodium butyrate and TSA to activate IL-18 gene expression.
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PMID:Differential effects of histone deacetylase inhibitors on interleukin-18 gene expression in myeloid cells. 1194 5

Normal IgM(-)IgD(+) CD38(+) B cells and IgM(-)IgD(+) multiple myelomas (MM) are characterized by Cmu deletion, biased Iglambda expression and hypermutated IgV regions. The predominant Iglambda usage has been proposed as resulting from secondary Ig gene rearrangements during extensive clonal expansion in the germinal center environment. Here, four cases of IgDlambda MM were studied to address the question of light chain receptor revision in a 'single cell' model. Detailed analyses of both IGK and IGL alleles of each case were performed by Southern blotting, (RT-) PCR, and sequencing. The expressed IgV genes were extensively mutated and Cmu deletion was confirmed in two cases. In addition, in the four MM a total of six non-functional deletional IGK rearrangements were identified, which proved to be unmutated. We conclude that IgD myelomas indeed originate from (post) germinal center B cells in which, in spite of the fact that they are hypermutated, there is no evidence of receptor revision.
Leukemia 2002 Jul
PMID:Biased Iglambda expression in hypermutated IgD multiple myelomas does not result from receptor revision. 1209 61

The general order of the immunoglobulin (Ig) gene rearrangement process in human precursor-B cells is largely known. However, the exact Ig rearrangement patterns reflecting this process, especially those of the Ig light chain genes, are not well established. This requires detailed analysis of the gene configuration of all six IGH, IGK and IGL alleles at the single cell level. As such extensive analyses are difficult to perform in a reliable way within a single normal precursor-B cell, we used 169 precursor-B-ALL (ie six pro-B-ALL, 112 common ALL, and 51 pre-B-ALL) as clonal 'single cell' model system. The Ig gene recombinations show hierarchy starting with IGH gene rearrangements in all cases, followed by IGK rearrangements, IGK deletions and/or IGL rearrangements in 71% of cases. IGK deletions were found in the absence of IGL rearrangements in 34% of cases, which might be explained by the continuous recombinase activity in precursor-B-ALL, resulting in 'end-stage' IGK rearrangements, together with an apparently limited accessibility of the IGL locus. Remarkably, in 5% of cases IGL rearrangements took place in the absence of IGK rearrangements. In addition we found that in-frame IGH rearrangements are not necessarily required for the induction of Ig light chain gene rearrangements and that IGL rearrangements can be induced irrespective of the frame of the accompanying IGK rearrangements. In conclusion, precursor-B-ALL constitute a model system for studying Ig gene rearrangement processes without selection for functionality of the rearrangements or the influence of somatic hypermutations. Nevertheless, the hierarchy of IGH, IGK and IGL rearrrangements is apparent in precursor-B-ALL.
Leukemia 2002 Aug
PMID:Immunoglobulin light chain gene rearrangements display hierarchy in absence of selection for functionality in precursor-B-ALL. 1214 84

Translocations involving the immunoglobulin loci are recurring events of B cell oncogenesis. The majority of translocations involve the immunoglobulin heavy chain (IGH) locus, while a minor part involves the immunoglobulin light chain loci consisting of the kappa light chain (IGK) located at 2p11.2 and the lambda light chain (IGL) located at 22q11.2. We characterised BAC clones, spanning the IGK and IGL loci, for detection of illegitimate rearrangements by fluorescence in situ hybridisation (FISH). Within the IGL region we have identified six end sequenced probes (22M5, 1152K19, 2036J16, 3188M21, 3115E23 and 274M7) covering the variable (IGLV) cluster and two probes (165G5 and 31L9) covering the constant (IGLC) cluster. Within the IGK region four probes (969D7, 316G9, 122B6 and 2575M21) have been identified covering the variable (IGKV) cluster, and one probe (1021F11) covering the IGK constant (IGKC) cluster. A series of 24 cell lines of different origin have been analysed for the presence of translocations involving the immunoglobulin light chain loci by dual-colour FISH where the split of the variable cluster and the constant cluster indicated a translocation. Probes established in this study can be used for universal screening of illegitimate rearrangements within the immunoglobulin light chain loci in B cell malignancies.
Leukemia 2002 Oct
PMID:Detection of illegitimate rearrangements within the immunoglobulin light chain loci in B cell malignancies using end sequenced probes. 1235 70

The retinoid receptors have major roles throughout development, even in the absence of ligand. Here, we summarize an emerging theme whereby gene repression, mediated by unliganded retinoid receptors, can dictate cell fate. In addition to activating transcription, retinoid receptors actively repress gene transcription by recruiting cofactors that promote chromatin compaction. Two developmental processes for which gene silencing by the retinoid receptors is essential are head formation in Xenopus and skeletal development in the mouse. Inappropriate repression, by oncogenic retinoic acid (RA)**Abbreviations used in this paper: APL, acute promyelocytic leukemia; dnRARalpha, dominant-negative version of the RARalpha; E, embryonic age; HDAC, histone deacetylase; LCoR, ligand-dependent corepressor; NCoR, nuclear receptor corepressor; RA, retinoic acid; RAR, RA receptor; RARE, RXR homodimer bound to bipartite response element; RXR, retinoid X receptor; TSA, trichostatin A; CYP26, cytochrome p450, 26; TR, thyroid hormone receptor. receptor (RAR) fusion proteins, blocks myeloid differentiation leading to a rare form of leukemia. Our current understanding of the developmental role of retinoid repression and future perspectives in this field are discussed.
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PMID:Active repression by unliganded retinoid receptors in development: less is sometimes more. 1271 67


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