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Results for “Gene Expression Regulation, Leukemic”

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At least 19 recordsLinked to original sources

PubMed2026

A tumor suppressor role of the miR-15b/16-2 cluster in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising from the neoplastic transformation of immature T cells during their development in the thymus. Deciphering the developmental programs whose dysregulation drives T-ALL pathogenesis is critical for the development of novel targeted therapies, which remain an urgent unmet need for the treatment of this disease. MicroRNAs (miRNAs) have emerged as key posttranscriptional regulators of numerous physiological processes, including cancer. However, the specific role of miRNAs in human T-cell development and T-ALL pathogenesis remains largely unexplored. In this study, we comprehensively evaluated miRNA expression profiles across human T-cell development using microarray analysis and identified a dynamic expression pattern of miR-16-2, which is upregulated during early pre-T-cell proliferative stages up to the resting stage of immature thymocytes immediately preceding T-cell receptor αβ expression and is subsequently downregulated. We also confirmed the coordinated regulation of miR-15b expression, consistent with the reported clustered genomic location of both miRNAs. Notably, functional studies identified the miR-15b/16-2 cluster as a negative regulator of early thymocyte proliferation and demonstrated that overexpression of miR-15b/16-2 in T-ALL cells impaired leukemic growth in vitro and tumor progression in patient-derived xenotransplantation assays. Mechanistically, miR-15b/16-2 represses the expression of the genes encoding BCL-2 and cyclin D3, thereby promoting apoptosis and cell cycle dysregulation in T-ALL cells, characterized by an accumulation of G0-phase cells and a defective transition to the G2/M phase. Overall, these findings support a novel tumor-suppressive function for miR-15b/16-2 in T-ALL and highlight its potential as a promising therapeutic target.

MicroRNAs↗

PubMed1992

Inhibition of specific pathways of myeloid cell differentiation by an activated Hox-2.4 homeobox gene.

Abnormal expression of homeobox genes is one of the abnormalities associated with the development of murine and human leukemia. Myeloid leukemic cells that can be induced to differentiate to mature cells by interleukin 6 were stably transfected with an activated Hox-2.4 homeobox gene. Expression of the Hox-2.4 gene in the transfected clones inhibited specific pathways of the myeloid differentiation program induced by interleukin 6. The expression of some genes associated with differentiation was almost completely blocked, and the expression of other genes was either partially inhibited or not affected. The results support the hypothesis that abnormal expression of Hox-2.4 may contribute to the development of leukemia by interfering with the differentiation program.

Animals↗

PubMed1992

Genomic organization of the putative human homeobox proto-oncogene HOX-11 (TCL-3) and its endogenous expression in T cells.

The HOX-11 (TCL-3) gene, which is abnormally expressed in the leukemic cells of some patients with T-cell acute lymphoblastic leukemia, is a new member of the homeobox gene family. It is structurally altered by the t(10;14) chromosomal translocation, resulting in head-to-tail juxtaposition of HOX-11 with the T-cell receptor delta-chain gene. In order to understand the normal functions of HOX-11 and its role in T-cell leukemia, we have determined the exon-intron structure of the HOX-11 gene. By using oligonucleotide primers flanking an intron of the HOX-11 gene, we have developed a quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay for the expression of HOX-11. We detected HOX-11 expression in multiple cell lineages including normal T cells and two T-cell lines in which the HOX-11 gene appeared to be unaltered in structure. Our results suggest that deregulation of the endogenous expression of HOX-11 in normal T cells represents an essential step towards the formation of this type of T-cell leukemia.

Amino Acid 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↗

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↗

PubMed1992

Abnormal regulation of the myc gene in myeloid leukemia.

To study the regulation of expression of the myc protooncogene, cells from normal individuals and patients with acute myelogenous leukemia (AML), and chronic phase and blastic crisis of chronic myeloid leukemia (CML) cells were put in overnight culture in the presence or absence of fetal calf serum. Myc expression in normal marrow cells and chronic phase CML cells fell after culture in vitro. In contrast, myc expression was maintained or increased in a majority of the AML and blastic crisis CML specimens. These data demonstrate that the regulation of myc expression is disordered in many AML and blastic crisis specimens but not in chronic phase CML cells.

Base Sequence↗

PubMed1992

Induction of the fms proto-oncogene product in HL-60 cells by vitamin D: a flow cytometric analysis.

Agents which induce monocytic characteristics in HL-60 human acute promyelocytic leukemia cells induce mRNA for the fms proto-oncogene, which encodes the receptor for M-CSF. Previous studies of fms expression in HL-60 cells have characterized chiefly induction by phorbol esters of fms mRNA. Our studies of fms expression in HI-60 cells have characterized induction by vitamin D3 of the fms protein. We have used flow cytometry to correlate fms antigen with a monocyte-specific differentiation antigen recognized by antibody MO2 (CD14), with DNA content, and with the nuclear antigen Ki-67, a marker of cell cycling. HL-60 cells were cultured with or without 1 microM vitamin D for 7 days. fms antigen was found on 42 +/- 5.8% of the cells cultured without vitamin D, but on 63 +/- 4.3% of the cells cultured with vitamin D. MO2 binding was detected on only 2 +/- 0.5% of the cells without vitamin D, but on 59 +/- 9% with vitamin D. Cells cultured with vitamin D that were fms-positive were also predominantly (83%) MO2-positive. Analysis of DNA content, measured by propidium iodide staining, showed that 57 +/- 1.5% of cells cultured without vitamin D, but 93 +/- 0.5% of cells cultured with vitamin D, were in the G0/G1 cell cycle phase. Analysis of nuclear antigen Ki-67 revealed that, of the vitamin D-treated cells that were fms-positive, a significant proportion (37%) were still cycling. We conclude that (1) fms is demonstrable on some uninduced HL-60 cells, (2) when HL-60 cells are induced to develop monocytic characteristics by vitamin D, fms induction is part of the program for monocytic differentiation that includes MO2 expression, yet (3) some induced cells expressing fms are still cycling.

Antigens, Differentiation↗

PubMed1992

Chromosome 21 rearrangement in acute biphenotypic leukemia.

A patient with myelodysplastic syndrome (MDS) and a 47,XY,+21 karyotype at diagnosis, was documented to have a clonal chromosome 21 rearrangement, i(21q), four months before transformation to acute biphenotypic leukemia. For 4 months after transformation, isochromosome 21 persisted while the patient was receiving treatment with zidovudine. Vitamin D3 was added to zidovudine for an additional month, during which time the trisomy 21 clone reappeared as the predominant cell population. The unique aspects of this patient are the atypical evolution of chromosome 21, the transformation to biphenotypic leukemia, and the occurrence of i(21q) associated with biphenotypic leukemia evolving from an MDS.

Anemia, Refractory, with Excess of Blasts↗

PubMed1992

P53 gene mutations in acute myelogenous leukaemia.

A polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assay was used to identify the exons which contained point mutations in the conserved regions (exons 4-8) of the p53 gene in 49 acute myelogenous leukaemia (AML) patients. SSCP analysis in our study was consistent with the results of subsequent direct DNA sequencing in detecting point mutational change in exons 5 and 8 of one AML patient and in exons 7 and 8 of two additional AML patients. The mutations were located at codons 245 and 273, which have been found in many other tumours, and codons 178 and 290, which have not been reported previously. All of the p53 proteins in which we detected point mutations were immunoprecipitated by the p53 monoclonal antibody PAb 240, which has been shown to recognize a mutant conformation of p53 protein. Thus, our results indicate that functional inactivation of the p53 gene by point mutational change might be one of the mechanisms underlying disease progression of AML.

Base Sequence↗

PubMed1992

RARA and PML genes in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation t(15;17). Recently, using molecular biology techniques, a number of laboratories have demonstrated that the gene coding for the retinoic acid receptor alpha (RARA), normally located on chromosome 17, is disrupted by the t(15;17) and fused with the PML gene on chromosome 15. The chromosome 17 breaks were mapped consistently within the second intron of the RARA gene while the chromosome 15 breaks were clustered in two limited regions within the PML gene. Molecular cloning and sequence analysis of the PML gene demonstrated a complex splicing pattern and this gene may encode a transcription factor. Different isoforms of the PML-RARA fusion transcripts were discovered which are produced as a result of distinct PML gene rearrangements. Sequence analysis of the reciprocal products of the translocation t(15;17) in some APL cases suggested the implication of topoisomerase II in mediating the DNA recombination. The RT/PCR procedure has been established to characterize the expression patterns of the PML-RARA fusion gene and to detect minimal residual disease (MRD). The biological activity of the PML-RARA fusion gene and its isoforms should be further explored.

Carrier Proteins↗

PubMed1992

In vivo infection of marrow stromal fibroblasts by feline leukemia virus.

Marrow stromal fibroblasts (FBs) likely play an important role in the regulation of hematopoiesis within the marrow microenvironment. Infection of these cells by feline leukemia virus (FeLV) might not only contribute to the pathogenesis of FeLV-induced hematologic diseases, but could provide a reservoir for virus in the infected cat. To determine the frequency of FeLV infection among marrow FB precursor cells (fibroblast colony-forming units, CFU-F) of cats viremic with FeLV-C/Sarma and FeLV-A/61E, marrow FBs and FB cell clones were isolated and assayed for expression of FeLV gag protein. From 30% to 86% and 64% to 88% of marrow FB precursors were infected with FeLV-C/Sarma and FeLV-A/61E, respectively. CFU-F from a cat viremic with FeLV-A/61E were not affected by exposure to antibody against FeLV envelope glycoprotein gp70 and heterologous complement, whereas similarly treated hematopoietic progenitors (erythroid colony-forming units, CFU-E; erythroid burst-forming units, BFU-E; and granulocyte-macrophage colony-forming units, CFU-GM) and culture-propagated, FeLV-infected marrow FBs were effectively lysed, suggesting that infected CFU-F within the marrow microenvironment do not express a significant amount of gp70 on their cell membranes. Thus, marrow FB precursor cells appear to be a major target for FeLV in vivo. Furthermore, the low level of gp70 antigen expression on the surface of these cells in vivo may allow them to escape immune surveillance and provide a reservoir of virus during active or latent infection.

Animals↗

PubMed1992

Differential expression of ras protooncogenes during in vitro differentiation of human erythroleukemia cells.

We have compared the expression of the ras protooncogene family (H-, K-, and N-ras) in leukemia cell differentiation utilizing as a model K562 and HEL erythroleukemia cells treated either with 1-beta-arabinofuranosylcytosine or 12-O-tetradecanoylphorbol-13-acetate (TPA). 1-beta-D-Arabinofuranosylcytosine induced terminal erythroid differentiation of K562 cells, while TPA induced myeloid differentiation of K562 and HEL cells, resulting in myelomonocytic-like cells expressing macrophagic and megakaryocytic markers. H-ras mRNA levels showed a dramatic decrease in K562 cells subjected to erythroid and myelomonocytic differentiation. The same result was found at the protein level for p21H-ras. Expression of K-ras and N-ras in K562 cells also decreased with differentiation, although significant mRNA levels remained despite cessation of cell proliferation. The decrease in K-ras expression was greater for TPA-treated cells than for 1-beta-arabinofuranosylcytosine-treated cells. TPA-induced myelomonocytic differentiation in HEL cells also resulted in a dramatic down-regulation of H-ras mRNA levels. Thus, by using a leukemia cell line able to differentiate along two different lineages, our results reveal a lineage-specific modulation of ras gene family expression.

Cell Differentiation↗

PubMed2025

DyNDG: Identifying Leukemia-related Genes Based on Time-series Dynamic Network by Integrating Differential Genes.

Leukemia is a malignant disease characterized by progressive accumulation with high morbidity and mortality rates, and investigating its disease genes is crucial for understanding its etiology and pathogenesis. Network propagation methods have emerged and been widely employed in disease gene prediction, but most of them focus on static biological networks, which hinders their applicability and effectiveness in the study of progressive diseases. Moreover, there is currently a lack of special algorithms for the identification of leukemia disease genes. Here, we proposed a novel Dynamic Network-based model integrating Differentially expressed Genes (DyNDG) to identify leukemia-related genes. Initially, we constructed a time-series dynamic network to model the development trajectory of leukemia. Then, we built a background-temporal multilayer network by integrating both the dynamic network and the static background network, which was initialized with differentially expressed genes at each stage. To quantify the associations between genes and leukemia, we extended a random walk process to the background-temporal multilayer network. The results demonstrate that DyNDG achieves superior accuracy compared to several state-of-the-art methods. Moreover, after excluding housekeeping genes, DyNDG yields a set of promising candidate genes associated with leukemia progression or potential biomarkers, indicating the value of dynamic network information in identifying leukemia-related genes. The implementation of DyNDG is available at both https://ngdc.cncb.ac.cn/biocode/tool/BT7617 and https://github.com/CSUBioGroup/DyNDG.

Leukemia↗

PubMed2025

Exploring prognostic genes in the immune microenvironment of acute myeloid leukemia via weighted gene co-expression network analysis.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous blood cancer that arises from transformed myeloid precursor cells in a compromised bone marrow microenvironment. This environment is essential for AML initiation, progression, and relapse. Alongside oncogenic changes in hematopoietic cells, immunological dysregulation also contributes to leukemogenesis. The present study is aimed to identify prognostic genes in stromal and immune cells associated with AML using the weighted gene co-expression network analysis (WGCNA). METHODS: Gene expression profiles were retrieved from The Cancer Genome Atlas database, and immune and stromal cell scores were calculated using the ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) method. These scores helped identify differentially expressed genes (DEGs), which were then used to create gene clusters through WGCNA. To explore the functions of genes linked to AML subtypes, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. A protein-protein interaction network was developed to identify hub genes. The top 18 hub genes were identified using the cytoHubba plug-in in Cytoscape software, and survival analysis was conducted with the Gene Expression Profiling Interactive Analysis 2 online tool. RESULTS: A total of 1097 DEGs were identified, with 601 being upregulated and 496 downregulated. WGCNA analysis indicated that the gray module, comprising 165 genes, had the strongest association with AML subtypes (Cor > 0.3; P < .05). Gene Ontology enrichment analysis demonstrated that the 18 identified hub genes were predominantly associated with neutrophil activation, immune response, secretory granule membrane, and pattern recognition receptor activity. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the DEGs were mainly involved in pathways related to phagosome, lysosome, tuberculosis, leishmaniasis, and neutrophil extracellular trap formation. Kaplan-Meier survival analysis of the top 18 hub genes indicated that ITGAM, IL10, and CD163 were significantly correlated with survival outcomes in AML. CONCLUSION: Key stromal and immune-related genes influencing AML patient outcomes were identified, highlighting their potential as therapeutic targets. These discoveries provide deeper insights into the molecular mechanisms driving AML pathogenesis and subtype differentiation.

Leukemia, Myeloid, Acute↗

PubMed1992

The differentiation pathway of HL60 cells is a model system for studying the specific regulation of some myeloid genes.

During granulopoiesis, certain myeloid genes encoding products of azurophilic granules are specifically down-regulated. The myeloid specific enzyme myeloperoxidase belongs to this group of genes. It is responsible for the production of hypochlorous acid, a potent microbicidal agent which is involved in host defense. During induced differentiation of promyelocytic leukemic HL60 cells to granulocyte- or monocyte-like cells, myeloperoxidase RNA is depressed. We studied this depression process in more detail by limiting the exposure to the inducer phorbol 12-myristate 13-acetate to 24 h. During this time period, no significant decrease in cell number and cell viability could be observed. Analysis of these in vitro differentiated HL60 cells on the protein and RNA levels showed that they can be used under defined conditions as a cell system to study the specific depression of myeloid genes. Under the described conditions, both the transcriptional rate of the myeloperoxidase gene as well as the stability of its transcript was reduced.

Actins↗

PubMed1992

Megakaryocytic leukemia and platelet factor 4.

The de novo megakaryocytic leukemia fulfilling the FAB criteria is still an uncommonly recognized variant of acute leukemia. Many studies have shown that the megakaryocytic leukemic events may occur at a pluripotent stem cell level and clinical observations reveal that the megakaryocytic leukemias are diverse entities. The immunophenotyping using monoclonal antibodies against platelet specific surface antigens and the ultrastructural detection of platelet peroxidase reaction do not provide sufficiently useful information to determine whether a megakaryocytic leukemia is chronic, acute, therapy-responsive or therapy-unresponsive. More sophisticated techniques are required to further characterize megakaryocytic leukemic cells. In this review, we emphasize that megakaryocytic leukemic cells can be categorized into two groups; one with the PF4 mRNA, and the other without it, and that the expression of PF4 mRNA in the blasts could be a useful marker for the identification of mature megakaryoblasts. It seems that the patients with blasts expressing PF4 mRNA will have a longer survival and a better response to chemotherapy than those without PF4. We further discuss the fact that the detection of mRNAs of the IL-6 receptor, PDGF A- and B-chains, and TGF beta 1 in megakaryocytic leukemic cells will be useful to clarify the mechanisms involved in the proliferation of megakaryocytic leukemic cells and fibroblasts in the bone marrow. Furthermore, we reviewed data showing that megakaryocytic erythroid, and mast cell lineages share the nuclear transcription factor known as GF-1 (NF-E1 or Erf-1). We suggest that characterization of megakaryocytic leukemia should be performed using monoclonal antibodies against erythroid, megakaryocytic and mast cell lineages.

Base Sequence↗

PubMed1992

Multidrug resistance (MDR) gene expression in acute non lymphoblastic leukemia: sequential analysis.

Sequential evaluation of P-glycoprotein expression was performed in 29 patients with acute nonlymphoblastic leukemia using immunocytochemistry with the C219 antibody. At diagnosis, 32% of the patients exhibited more than 5% of the P-gp(+) leukemic cells. Under chemotherapy, 62% of the patients eventually expressed a subset of P-gp positive leukemic cells. After conventional doses of cytosine-arabinoside (Ara-C) and daunorubicin or mitoxantrone, positive P-gp cells were noted in 65% of the cases. This percentage was significantly higher (p = 0.002) than the proportion of positive cases (15%) observed after regimens containing either intermediate doses of Ara-C or cyclosporine A, a P-gp modulator.

ATP Binding Cassette Transporter, Subfamily B, Mem↗