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At least 181 records · Page 10Linked to original sources
PubMed1997

Transient expression of M-CSF is important for osteoclast-like cell differentiation in a monocytic leukemia cell line.

Cells of U937, a human monocytic leukemia cell line, differentiate into macrophages by treatment with 12-o-tetradecanoylphorbol-13-acetate (TPA), whereas cells treated with 1 alpha, 25-dihydroxyvitamin D3 [1,25-(OH)2D3] continue to grow without undergoing differentiation. When U937 cells were successively treated with TPA and 1,25-(OH)2D3, tartrate-resistant acid phosphatase-positive multinucleated cells appeared at 5 days after the treatment. These osteoclast-like cells released a soluble form of 45Ca from 45Ca-labeled bone particles. These cells were not formed when the order of treatment with TPA and 1,25-(OH)2D3 was reversed. Use of either dexamethasone or interferon-gamma (IFN-gamma) was effective in inhibiting the formation of these osteoclast-like cells. The expression of c-src, c-fms, and macrophage colony stimulating factor (M-CSF) was induced by TPA treatment; however, TPA-induced M-CSF gene transcription was attenuated by the subsequent addition of 1,25-(OH)2D3. Furthermore, both dexamethasone and IFN-gamma impaired the attenuation of M-CSF expression, suggesting that the transient expression of M-CSF may be important for the formation of osteoclast-like cells.

Acid Phosphatase↗
PubMed2007

Aberrant expression of T-cell-associated markers CD4 and CD7 on B-cell chronic lymphocytic leukemia.

By multiparameter flow cytometry, the T-cell-associated markers CD4 and CD7 were aberrantly coexpressed on a case of B-cell chronic lymphocytic leukemia (CLL). The CLL had an immunophenotype: CD19+, CD20+, CD79b+, CD5+, CD23+, FMC7+, kappa+, CD4+, and CD7+. Molecular analysis confirmed clonal rearrangement of the immunoglobin heavy chain genes and a germline configuration of the T-cell receptor genes. Fluorescence in situ hybridization showed trisomy 12 anomaly. There was no evidence of deletion 17p (p53), 11q23 (ATM), or 13q14 or translocation t(11:14). The patent was clinically stable without treatment. Although the pathogenesis of such aberrant immunophenotype remains to be determined, the current case illustrates the phenotypic heterogeneity of CLL, and emphasizes the importance of a comprehensive diagnostic approach including clinical, morphologic, immunophenotypic, and molecular cytogenetic studies.

Aged↗
PubMed1992

Protooncogene expression in subpopulations of cells from leukemia patients.

This report describes a method for preserving the light scatter patterns of cells in which myc and myb expression are being measured. Exposure of cells to 1% paraformaldehyde for 72 h prior to antibody staining for myc and myb proteins preserved the light scatter patterns. Using this method, myc and myb expression was found to be highest in lymphocytes and monocytes and lowest in granulocytes. The measurement of differences in the level of expression of these genes in subpopulations of leukemia cells obtained from individual patients is possible as is assessment of the levels of expression amongst normal and leukemia cells present in the same patient.

Bone Marrow↗
PubMed1991

The LCK gene is involved in the t(1;7)(p34;q34) in the T-cell acute lymphoblastic leukemia derived cell line, HSB-2.

HSB-2 is a cell line derived from a patient who had T-cell acute lymphoblastic leukemia (T-cell ALL) with a t(1;7)(p34;q34). We used a genomic probe from the T-cell receptor beta (TCR beta) locus (7q34) to identify DNA rearrangements in HSB-2. Two rearranged BglII DNA fragments were cloned, and one of these clones was shown to contain the translocation breakpoint on the derivative chromosome I [der(I)]. We used a probe derived from this clone to isolate an unrearranged phage clone encompassing the breakpoint at Ip34. The restriction map of this clone was compared to the published maps of known protooncogenes located at Ip32-34. By restriction mapping, Southern blot analysis, and DNA sequencing we showed that the translocation breakpoint on chromosome I is located within the first intron of the LCK gene. The LCK gene codes for p56lck, a member of the SRC family of cytoplasmic tyrosine protein kinases. There are two classes of LCK transcripts (type I and type II), each expressed from a distinct promoter, and each having a unique 5' untranslated region (UTR); the protein coding regions of the two classes are identical. The breakpoint in the t(1;7) separates the two LCK promoters and juxtaposes the constant region of the TCR beta locus with the proximal promoter and with the protein-coding region of the LCK gene on the der(I) chromosome.

Base Sequence↗
PubMed1992

Karyotype and T-cell receptor expression in T-lineage acute lymphoblastic leukemia.

The relationship between karyotype and expression of the T-cell receptor (TCR) proteins was examined in 19 patients with T-lineage acute lymphoblastic leukemia (T-ALL). All patients expressed CD3 molecules in the cytoplasm or on the cell membrane. Patients were classified according to TCR expression thus: no TCR expression (TCR-), six cases; cytoplasmic expression of TCR beta chain (cTCRB) only, six cases; membrane expression of TCR alpha and beta chains (mTCRAB), five cases; membrane expression of TCR gamma and delta (mTCRGD), two cases. A chromosomally abnormal clone was detected in 15 cases. The most common site of chromosomal change was at 14q11 (seven cases), the chromosomal band to which TCRA and TCRD have been mapped; as a deletion (two cases); or as a translocation with reciprocal breakpoints in bands containing the TCRG (7p15); TCRB (7q35); or putative oncogenes HOXII (10q24), RBTN2 (11p13) or MYC (8q24) genes. Breakpoints were also seen in 6q (three cases), 9p (two cases), or 11q23 (two cases). The following observations were made: All four chromosomally normal cases lacked TCR expression (TCR-). Breakpoints at 14q11 were found in one of six TCR- cases, four of six cTCRB cases, and two of five mTCRAB cases. Abnormalities of 6q and of 9p were seen only in cases with full TCR expression (mTCRAB or mTCRGD).

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Localization of the fibroblast growth factor receptor-4 gene to chromosome region 5q33-qter.

Our polymerase chain reaction cloning of novel tyrosine kinases expressed in the K562 chronic myeloid leukemia cells has revealed a novel fibroblast growth factor receptor, FGFR4. We have here mapped the FGFR4 gene by analysis of somatic cell hybrids and in situ hybridization to the 5q33-qter chromosomal region. This finding is of interest in that the FGFR4 gene is expressed in several leukemia cell lines and the 5q33-qter region is involved in nonrandom chromosomal translocations in acute myelogenous leukemias and Ki-I lymphomas.

Chromosome Mapping↗
PubMed1994

DNA rearrangements and altered transcripts of the MLL gene in a human T-ALL cell line Karpas 45 with a t(X;11) (q13;q23) translocation.

Translocations involving chromosome band 11q23 are found in both lymphoid and myeloid leukemias as well as in lymphomas, in these translocations. The chromosomes most frequently involved in reciprocal translocations include chromosomes 4, 6, 9, and 19, and we and others have reported that chromosomes 1, 2, 10, 15, 17, 18, 22, and X are also involved. In the cell line Karpas 45, which has a t(X;11) (q13;q23) translocation, we report here that the MLL gene is rearranged and that there are two altered transcripts of MLL that come from the der(11) chromosome.

Chromosomes, Human, Pair 11↗
PubMed2006

Analysis of immunoglobulin heavy and light chain variable genes in post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLD) derive from antigen-experienced B-cells and represent a major complication of solid organ transplantation. We characterized usage, mutation frequency and mutation pattern of immunoglobulin variable (IGV) gene rearrangements in 50 PTLD (polymorphic PTLD, n=10; diffuse large B-cell lymphoma, n=35; and Burkitt/Burkitt-like lymphoma, n=5). Among PTLD yielding clonal IGV amplimers, a functional IGV heavy chain (IGHV) rearrangement was found in 40/50 (80.0%) cases, whereas a potentially functional IGV light chain rearrangement was identified in 36/46 (78.3%) PTLD. By combining IGHV and IGV light chain rearrangements, 10/50 (20.0%) PTLD carried crippling mutations, precluding expression of a functional B-cell receptor (BCR). Immunohistochemistry showed detectable expression of IG light chains in only 18/43 (41.9%) PTLD. Failure to detect a functional IGV rearrangement associated with lack of IGV expression. Our data suggest that a large fraction of PTLD arise from germinal centre (GC)-experienced B-cells that display impaired BCR. Since a functional BCR is required for normal B-cell survival during GC transit, PTLD development may implicate rescue from apoptosis and expansion of B-cells that have failed the GC reaction. The high frequency of IGV loci inactivation appears to be a peculiar feature of PTLD among immunodeficiency-associated lymphoproliferations.

Apoptosis↗
PubMed2005

Transcriptional activation of survivin through the NF-kappaB pathway by human T-cell leukemia virus type I tax.

Survivin, a unique member of the inhibitor of apoptosis protein family, is overexpressed in many cancers and considered to play an important role in oncogenesis. We previously reported the survivin expression profile in ATL, a CD4-positive T-cell malignancy caused by HTLV-I. HTLV-I Tax is thought to play an important role in immortalization of T cells. We have shown also that the expression of Tax protected the mouse T-cell line CTLL-2 against apoptosis induced by deprivation of IL-2 and converted its growth from being IL-2 dependent to being IL-2 independent through the NF-kappaB pathway. In our study, we demonstrate that constitutive expression of survivin was associated with resistance to apoptosis after IL-2 deprivation in Tax-expressing CTLL-2 cells. Transient transfection assays showed that survivin promoter was transactivated by Tax, via the activation of NF-kappaB. Pharmacological NF-kappaB inhibition resulted in suppression of survivin expression and caused apoptosis of Tax-expressing CTLL-2 cells. Our findings suggest that activated NF-kappaB signaling contributes directly to malignant progression of ATL by preventing apoptosis, acting through the prosurvival protein survivin.

Animals↗
PubMed2003

TP53 is frequently altered by methylation, mutation, and/or deletion in acute lymphoblastic leukaemia.

Different mechanisms, such as chromosomal rearrangements, deletions, mutations, and methylation/demethylation of the promoter regions of genes, have been shown to be involved in acute lymphoblastic leukaemia (ALL). These genetic and epigenetic alterations lead to the activation of protooncogenes or to inactivation of tumour suppressor genes promoting cell proliferation. One of the most frequently inactivated tumour suppressor genes is TP53, which is altered in 50% of human tumours. In this study, we have analysed: (1) the complete coding region, all intron-exon junctions and noncoding regions of exons 1-11 of TP53 by lexon-DGGE; (2) the methylation status of the 5' region of TP53 and (3) the deletion of one or both alleles of the gene by fluorescence in situ hybridisation (FISH) in 57 ALL patients. Using these techniques, we have found promoter methylation in 32% of the cases, missense mutations in 8.8%, and deletion of one allele in 7.5% of the samples, with TP53 being altered in 40% of the ALL samples studied in this series.

CpG Islands↗
PubMed2026

Sodium Overload-Related Molecular Subtypes and a Four-Gene Prognostic Signature Predict Survival, Immune Landscape, and Therapeutic Response in Acute Myeloid Leukemia.

Sodium overload has recently emerged as a critical metabolic stressor involved in cancer progression; however, its molecular characteristics and clinical relevance in acute myeloid leukemia (AML) remain unexplored. RNA-seq data sets, clinical annotations, and mutational profiles of AML patients were annotations from The Cancer Genome Atlas and integrated with Genotype-Tissue Expression normal samples. Sodium overload-related genes (SORGs) were obtained from GeneCards. Differentially expressed SORGs (DESORGs) screened by applying the limma statistical model, followed by univariate Cox proportional hazards regression, consensus clustering, functional enrichment, immune infiltration analysis, and pathway evaluation. A prognostic signature was developed through least absolute shrinkage and selection operator regression followed by multivariate Cox modeling. The model's performance was further verified in two external GEO data sets (GSE71014 and GSE37642). Nomogram construction, subgroup analysis, tumor mutational burden (TMB) assessment, drug sensitivity prediction, transcription factor (TF) analysis, and competing endogenous RNA (ceRNA) network analyses were also performed. A total of 57 DESORGs were identified, and 2 sodium overload-related molecular subtypes exhibited distinct survival, immune infiltration, and inflammatory pathway activation. A robust four-gene signature (DOCK1, GABRE, HTR7, ACSM1) stratified patients into high- and low-risk categories with significantly different survival across training and validation cohorts. High-risk patients displayed increased immune infiltration, higher TMB, reduced sensitivity to multiple chemotherapeutic drugs, and inferior predicted response to PD-L1 blockade. TF and ceRNA networks revealed multilayered transcriptional and post-transcriptional regulation of the signature genes. This study identifies sodium overload-related molecular heterogeneity in AML and establishes a validated four-gene prognostic signature that integrates genomic, immunologic, and therapeutic features, offering potential utility for personalized risk assessment and treatment optimization.

Humans↗
PubMed2007

Prognostic significance of WT1 gene expression in pediatric acute myeloid leukemia.

BACKGROUND: The Wilms Tumor gene (WT1) encodes a transcription factor involved in kidney development and malignancy. WT1 expression in a subpopulation of early CD34+ cells has suggested its involvement in hematopoiesis. WT1 is aberrantly expressed in leukemias. High expression of WT1 at diagnosis has been associated with unfavorable prognosis in adult acute myeloid leukemia (AML). The prognostic relevance of WT1 expression in pediatric AML was evaluated in only one study, including 47 patients, which showed that very low levels of WT1 at presentation were associated with an excellent outcome. To test the validity of these findings we measured levels of WT1 in 41 newly diagnosed pediatric AML of the non-M3 FAB subtype. PROCEDURE: Patients were treated according to an AML-BFM 83-based protocol in a single institution. Mononucleated cells obtained from presentation BM aspirates were cryopreserved and later thawed and used for total RNA extraction and cDNA synthesis. The quantitative assessment of WT1 transcripts was made by real-time PCR (RQ-PCR). WT1 transcripts values were normalized with respect to the number of ABL transcripts. RESULTS: WT1 levels were significantly higher in patients bearing favorable chromosome abnormalities, t(8;21) and inv(16) (P = 0.002). Higher levels of WT1 expression were unexpectedly associated with a higher probability of overall survival by Cox regression analysis (P = 0.002). Multivariate regression analysis could not discriminate between the effects of WT1 and cytogenetics on survival. CONCLUSIONS: Higher WT1 expression was associated with favorable cytogenetics subtypes and accordingly with better outcome in children with AML in this study.

Acute Disease↗
PubMed1998

Identification of upstream regulatory elements that repress expression of adult beta-like globin genes in a primitive erythroid environment.

Our investigations have focused on localizing cis-elements responsible for the down regulation of the adult beta-like globin genes (delta and beta) in immature, or primitive erythroid tissues. We studied their activity after transfection into K562 cells, an erythroleukemia cell line with an embryonic-fetal phenotype. Analyzed DNA sequences included delta and beta 5' flanking regions extending from approximately -500 to +50bp (promoter regions), truncated delta and beta 5' flanking regions extending from approximately -250 to +50 bp, and chimeric promoter constructions, which consisted of a distal delta or beta fragment fused to a proximal beta or delta sequence. In CAT reporter constructions no appreciable level of CAT activity was supported by the beta globin promoter, and only low level activity by the delta promoter. Truncation of the beta globin promoter led to a 2-3 fold increase in promoter activity. In contrast, deletion of the upstream portion of the delta promoter led to a 10 fold decrease in expression. Coupling of the upstream beta globin sequence from approximately -500 to -250 bp to the truncated delta promoter fragment led to complete extinction of transcription activity, consistent with a negative regulatory effect of the beta globin gene upstream element(s). Fusion of the upstream portion of the delta promoter to the truncated beta globin promoter yielded a modest increase in promoter strength relative to the truncated beta gene promoter, indicating the presence of a positive transcriptional element(s) in the upstream delta globin regulatory region. Site-directed mutagenesis of binding sites for the repressor proteins BP1 and BP2 in the upstream portion of the beta globin gene flanking region led to a 4-6 fold increase in promoter activity. DNase I footprinting of the upstream delta-globin region revealed protected sequences corresponding to consensus binding sites for GATA-1 and BP2. These results confirm that sequences in the upstream promoter region of the adult beta globin gene contribute to its factor-mediated suppression early in development and then may modulate its expression at a later stage.

Binding Sites↗
PubMed1996

A novel transcript encoded within the 10-kb first intron of the human p53 tumor suppressor gene (D17S2179E) is induced during differentiation of myeloid leukemia cells.

Two promoters were previously shown to map to the 5'-end of the human p53 gene. p53p1 was located upstream of the first exon and is responsible for transcription of the major p53 mRNA species. p53p2 is a stronger promoter than p53p1 and was located within the 10, 738-bp first intron, approximately 1000 bp downstream of exon 1. mRNA transcripts that initiated from p53p2 were previously identified in HL-60 cells by primer extension analysis and were observed to increase in abundance during differentiation of HL-60 cells to granulocytes. By screening a cDNA library with a probe derived from sequences downstream of the p53p2 start site, we have cloned and characterized a cDNA that represents a mRNA that appears to have been initiated from the p53p2 promoter. We have designated the gene encoding this transcript Hp53int1 (the GDB designation is D17S2179E). The cDNA is 1125 bp and is polyadenylated downstream from a consensus poly(A) addition site. The entire 1125 bp is derived from intron 1 of the p53 gene, with no introns having been removed. The cDNA contains no major open reading frame although reading frame +1 contains a relatively low abundance of stop codons compared to the other two reading frames and could possibly encode a protein of 119 amino acids. Analysis of the +1 reading frame shows a region of high homology to a portion of the DNA-binding domain of NF-kappaB. These results indicate that a novel polyadenylated transcript is encoded by the first intron of the human p53 gene. Hp53int1 may be a pseudogene for a gene that may have encoded a DNA-binding protein. Alternatively, the transcript may have a function, since RNA transcripts of this gene are present in a number of human cells and their levels are induced during terminal differentiation of myeloid leukemia cells such as HL-60 and U937.

Amino Acid Sequence↗
PubMed1993

Pharmacological modulation of c-fos mRNA expression in the HL60 and U937 cell lines.

A variety of drugs known to act via increasing intracellular cAMP are used in the treatment of asthma. In this study we asked whether anti-asthma drugs are capable of altering gene activation. We determined whether phosphodiesterase inhibitors, either alone or in combination with adrenoceptor agonists, were able to alter the abundance of mRNA of the cAMP responsive gene c-fos in the cell-lines HL60 and U937. Incubation of cells with phosphodiesterase inhibitors aminophylline, theophylline or pentoxyphylline all resulted in an increase in c-fos mRNA. Further upregulation of c-fos mRNA abundance was observed when the cells were stimulated with the combination of aminophylline and adrenoceptor agonists with beta 2-agonist activity. These increases in c-fos mRNA were accompanied by increases in intracellular concentration of cAMP. These data suggest that in these in vitro models, combinations of beta 2-adrenoceptor agonists and phosphodiesterase inhibitors can increase intracellular cAMP and affect gene activation.

Adrenergic beta-Agonists↗