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)

Children with Down syndrome (DS) have a 10- to 20-fold increased risk of developing acute leukemia. An estimated 10% of newborns with DS develop Transient Myeloproliferative Disease (TMD) or Transient Leukemia (TL), a clonal accumulation of megakaryoblasts that resolves spontaneously within months. Acute megakaryoblastic leukemia (AMKL) develops in approximately 20% of cases of TMD/TL by 4 years of age. Both the blasts of AMKL and TMD/TL in DS harbor somatic mutations of GATA1, an essential transcriptional regulator of megakaryocytic differentiation. The distinct phenotypes of megakaryoblastic leukemia in DS are a unique biological model of the incremental process of leukemic transformation.
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PMID:Acute megakaryoblastic leukemia in Down syndrome. 1794 65

Shiga toxins (Stxs) expressed by the enteric pathogens Shigella dysenteriae 1 and enterohaemorrhagic Escherichia coli are potent protein synthesis inhibitors. Shiga toxins have also been shown to induce apoptosis in epithelial, endothelial and monocytic cells. The precise relationship between protein synthesis inhibition and induction of apoptosis is not known. We show that stimulation of the myelogenous leukaemia cell line THP-1 with purified Stx1 induced the endoplasmic reticulum (ER) stress response. Stx1 treatment increased activation of the ER stress sensors IRE1, PERK and ATF6. Toxin treatment increased expression of the transcriptional regulator CHOP and the death domain-containing receptor DR5 at mRNA and protein levels. Following Stx1 intoxication, levels of the survival factor Bcl-2 decreased, while secretion of the death-inducing ligand TRAIL increased. Stx1 enzymatic activity was required for optimal activation of PERK and ATF6, but not IRE1. ER stress elicited by Stx1 increased the release of Ca(2+) from ER stores and the activation of the protease calpain. Inhibition of calpain activity led to reductions in Stx1-induced cleavage of procaspase-8 and apoptosis. Collectively, these data suggest that Shiga toxins trigger monocytic cell apoptosis through the ER stress response, the increased expression of DR5 and TRAIL, and activation of caspase-8 via a calpain-dependent mechanism.
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PMID:Shiga toxin 1 induces apoptosis through the endoplasmic reticulum stress response in human monocytic cells. 1800 43

MicroRNAs (miRNAs) are short 20-22 nucleotide RNA molecules that act as negative regulators of gene expression via translational repression: they have been shown to play a role in development, proliferation, stress response, and apoptosis. The transcriptional regulator LRF (Leukemia/lymphoma Related Factor) has been shown to prevent p19ARF transcription and consequently to inhibit senescence in mouse embryonic fibroblasts (MEF). Here we report, for the first time, that LRF is post-transcriptionally regulated by miR-20a. Using a gene reporter assay, direct interaction of miR-20a with the LRF 3'UTR is demonstrated. To validate the interaction miR-20a/3'UTR LRF miR-20a was over-expressed, either by transient transfection or retroviral infection, in wild type mouse embryo fibroblasts and in LRF-null MEF derived from LRF knock-out mice. We observed LRF decrease, p19ARF increase, inhibition of cell proliferation and induction of senescence. The comparison of miR-20a activity in wt and LRF-null MEF indicates that LRF is the main mediator of the miR-20a-induced senescence and that other targets are cooperating. As LRF down-regulation/p19ARF induction is always accompanied by E2F1 down-regulation and increase of p16, we propose that all these events act in synergy to accomplish miR-20a-induced senescence in MEF. Senescence has been recently revaluated as a tumor suppressor mechanism, alternative to apoptosis; from this point of view the discovery of new physiological "senescence inducer" appears to be promising as this molecule could be used as anticancer drug.
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PMID:The proto-oncogene LRF is under post-transcriptional control of MiR-20a: implications for senescence. 1859 85

The small RNAs include siRNA and miRNA. SiRNA is the splicing product of exogenous dsRNA by which to keep genome stability, while miRNA are processed from endogenous genome and work as a post-transcriptional regulator for gene expression. The small RNAs act in two ways: mediate degradation of of target RNA and inhibit translation of protein. The former requires the accurate complementation between small RNA and target RNA, while the latter requires only partial complementation. Which mechanism used depends on complementation degree, but not their origins. The RNAi as a technique for down-regulating target gene expression has been widely used in functional genomic studies and hematologic studies, especially for translocation-related fusion gene, apoptosis-related gene and MDR gene in leukemia. The results show that RNAi technique not only is the powerful tool for study mechanism but also has therapeutic potentials in clinic. Some studies reveal that changes of miRNA expression exist in many hematological malignancies and relate to known oncogenes, which indicates the miRNA is involved in pathogenesis of these diseases. This article reviews the discovery and effect of RNAi and small RNAs, as well as the similarities and differences between siRNA and miRNA, and focuses on the research of small RNAs in hematological malignancies.
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PMID:[Recent advances on application of small RNA in research for hematological malignancies - review]. 1892 36

The human Mixed-Lineage-Leukemia-5 (MLL5) gene is located in a genomic region frequently deleted in patients with myeloid malignancies and encodes a widely expressed nuclear protein most closely related to MLL1, a Trithorax transcriptional regulator with established involvement in leukemogenesis. Although the physiologic function of MLL5 is completely unknown, domain structure and homology to transcriptional regulators with histone methyltransferase activity suggest a role in epigenetic gene regulation. To investigate physiologic functions of Mll5, we have generated a knockout mouse mutant using Cre/loxP technology. Adult homozygous Mll5-deficient mice are obtained at reduced frequency because of postnatal lethality. Surviving animals display a variety of abnormalities, including male infertility, retarded growth, and defects in multiple hematopoietic lineages. Interestingly, Mll5(-/-) mice die of sublethal whole-body irradiation but can be rescued with wild-type bone marrow grafts. Flow cytometric ana-lysis, bone marrow reconstitution, and in vivo BrdU-labeling experiments reveal numerical, functional, and cell-cycle defects in the lineage-negative Sca-1(+), Kit(+) (LSK) population, which contains short- and long-term hematopoietic stem cells. Together, these in vivo findings establish several nonredundant functions for Mll5, including an essential role in regulating proliferation and functional integrity of hematopoietic stem/progenitor cells.
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PMID:Impaired function of primitive hematopoietic cells in mice lacking the Mixed-Lineage-Leukemia homolog MLL5. 1922 Oct 41

The mixed-lineage leukemia protein MLL1 is a transcriptional regulator with an essential role in early development and hematopoiesis. The biological function of MLL1 is mediated by the histone H3K4 methyltransferase activity of the carboxyl-terminal SET domain. We have determined the crystal structure of the MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide. This structure indicates that, in order to form a well-ordered active site, a highly variable but essential component of the SET domain must be repositioned. To test this idea, we compared the effect of the addition of MLL complex members on methyltransferase activity and show that both RbBP5 and Ash2L but not Wdr5 stimulate activity. Additionally, we have determined the effect of posttranslational modifications on histone H3 residues downstream and upstream from the target lysine and provide a structural explanation for why H3T3 phosphorylation and H3K9 acetylation regulate activity.
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PMID:Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks. 1918 61

Accumulating genetic and functional evidence point to ETV6 as being the tumour suppressor gene targeted by the deletions at chromosome 12p12-13 found in various cancers, particularly childhood leukemia. ETV6 is a ubiquitously expressed transcription factor (TF) of the ETS family with very few known targeted genes. We recently compiled a list of 87 ETV6-modulated genes that can be classified into a number of subgroups based on their coordinated expression patterns. In the present report, we hypothesized that genes presenting a similar profile of modulation could also share biological features, promoter sequence similarities and/or, common transcription factor binding sites (TFBSs). Using an exploratory approach based on hierarchical clustering of expression data, Gene Ontology (GO) terms, sequence similarity and evolutionary conserved putative TFBSs, we found that many genes presenting a similar expression profile also share biological features and/or conserved predicted TFBSs but rarely show detectable promoter sequence similarities. We also calculated the proportion of ETV6-modulated genes that have any conserved TFBSs of the Jaspar database in their regulatory sequence and compared these proportions to those calculated for two other gene lists, ETV6 non-modulated and ETS-regulated. We found that the NF-kB, c-REL and p65 TFBSs, which all bind TFs of the REL class, were under-represented among the ETV6-modulated genes compared to the ETV6-non-modulated genes, while the Broad-complex 1 TFBS appeared to be over-represented. NF-Y and Chop/cEBP TFBSs were over-represented in the promoters of ETV6-modulated genes compared to ETS-regulated genes. These analyses will help direct further studies intending to understand the role of ETV6 as a transcriptional regulator and aid in constructing the ETV6-regulatory gene network.
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PMID:Connections between ETV6-modulated genes: identification of shared features. 1925 10

Terminal differentiation of blood cells requires the concerted action of a series of transcription factors that are expressed at specific stages of maturation and function in a cell-type and dosage-dependent manner. Leukemogenic oncoproteins block differentiation by subverting the normal transcriptional status of hematopoietic precursor cells. Pirin (PIR) is a putative transcriptional regulator whose expression is silenced in cells bearing the acute myeloid leukemia-1 eight-twenty-one (AML1/ETO) and promyelocytic leukemia/retinoic acid receptor (PML/RAR) leukemogenic fusion proteins. A role for PIR in myeloid differentiation has not to date been reported. In this study we show that PIR expression is significantly repressed in a large proportion of acute myeloid leukemias (AMLs), regardless of subtype or underlying karyotypic abnormalities. We show that PIR expression increases during in vitro myeloid differentiation of primary hematopoietic precursor cells, and that ablation of PIR in the U937 myelomonocytic cell line or in murine primary hematopoietic precursor cells results in impairment of terminal myeloid differentiation. Gene expression profiling of U937 cells after knockdown of PIR revealed increased expression of genes associated with the early phases of hematopoiesis, in particular, homeobox A (HOXA) genes. Our results suggest that PIR is required for terminal myeloid maturation, and its downregulation may contribute to the differentiation arrest associated with AML.
Leukemia 2010 Feb
PMID:Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation. 2001 Jun 24

The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix protein that belongs to the superfamily of environment-sensing PAS (Per-ARNT-Sim) proteins. A large number of ligands have been described to bind AhR and promote its nuclear translocation. In the nucleus, the AhR and its dimerization partner the AhR nuclear translocator (ARNT) form a DNA-binding complex that acts as a transcriptional regulator. Animal and human data suggest that, beyond its mediating responses to xenobiotic and/or unknown endogenous ligands, the AhR has a role, although as yet undefined, in the regulation of cell cycle and inflammation. The AhR also appears to regulate the hematopoietic and immune systems during development and adult life in a cell-specific manner. While accidental exposure to xenobiotic AhR ligands has been associated with leukemia in humans, the specific mechanisms of AhR involvement are still not completely understood. However, recent data are consistent with a functional role of the AhR in the maintenance of hematopoietic stem and/or progenitor cells (HSCs/HPCs). Studies highlighting AhR regulation of HSCs/HPCs provide a rational framework to understand their biology, a role of the AhR in hematopoietic diseases, and a means to develop interventions for these diseases.
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PMID:The aryl hydrocarbon receptor: regulation of hematopoiesis and involvement in the progression of blood diseases. 2017 Nov 26

The lmo2 gene is a specific oncogene in T-cell leukemia, for its ectopic expression causes both increased pro-T-cell proliferation and differentiation arrest, leading to the onset of leukemia. Notably, DeltaEF1 (also known as ZEB1), a member of zinc finger-homeodomain family transcription factor, also exhibits crucial function in promoting T-cell differentiation. In this study, we found that DeltaEF1 was positively regulated by T-lineage-specific transcriptional regulator GATA3, while ectopically expressed LMO2 targeted to DeltaEF1 promoter by interaction with GATA3 and inhibited DeltaEF1 expression in transcriptional level. Moreover, LMO2 interacted with the N-terminal zinc finger domain of DeltaEF1 protein and inhibited its positive transcriptional regulatory function by this interaction. Taken together, our findings revealed that ectopically expressed LMO2 impaired the function of DeltaEF1 in both transcriptional and protein levels and identified DeltaEF1 as a novel pathogenic target of LMO2 in T-cell leukemia.
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PMID:Identification of DeltaEF1 as a novel target that is negatively regulated by LMO2 in T-cell leukemia. 2073 4


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