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)

The Runt domain transcription factors (RUNXs) play essential roles in normal development and neoplasias. Genetic analyses of animals and humans have revealed the involvement of RUNX1 in hematopoiesis and leukemia, RUNX2 in osteogenesis and cleidocranial dysplasia, and RUNX3 in the development of T-cells and dorsal root ganglion neurons and in the genesis of gastric cancer. Here we report that RUNX3 is a target of the acetyltransferase activity of p300. The p300-dependent acetylation of three lysine residues protects RUNX3 from ubiquitin ligase Smurf-mediated degradation. The extent of the acetylation is up-regulated by the transforming growth factor-beta signaling pathway and down-regulated by histone deacetylase activities. Our findings demonstrate that the level of RUNX3 protein is controlled by the competitive acetylation and deacetylation of the three lysine residues, revealing a new mechanism for the posttranslational regulation of RUNX3 expression.
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PMID:Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. 1513 60

Runt-related (RUNX) gene family is composed of three members, RUNX1/AML1, RUNX2 and RUNX3, and encodes the DNA-binding (alpha) subunits of the Runt domain transcription factor polyomavirus enhancer-binding protein 2 (PEBP2)/core-binding factor (CBF), which is a heterodimeric transcription factor. RUNX1 is most frequently involved in human acute leukemia. RUNX2 shows oncogenic potential in mouse experimental system. RUNX3 is a strong candidate as a gastric cancer tumor suppressor. The beta subunit gene of PEBP2/CBF is also frequently involved in chromosome rearrangements associated with human leukemia. In this Overview, I will summarize how this growing field has been formed and what are the challenging new frontiers for better understanding of the oncogenic potential of this gene family.
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PMID:Oncogenic potential of the RUNX gene family: 'overview'. 1515 73

RUNX family members are DNA-binding transcription factors that regulate the expression of genes involved in cellular differentiation and cell cycle progression. The RUNX family includes three mammalian RUNX proteins (RUNX1, -2, -3) and two homologues in Drosophila. Experiments in Drosophila and mouse indicate that the RUNX proteins are required for gene silencing of engrailed and CD4, respectively. RUNX-mediated repression involves recruitment of corepressors such as mSin3A and Groucho as well as histone deacetylases. Furthermore, RUNX1 and RUNX3 associate with SUV39H1, a histone methyltransferase involved in gene silencing. RUNX1 is frequently targeted in human leukemia by chromosomal translocations that fuse the DNA-binding domain of RUNX1 to other transcription factors and corepressor molecules. The resulting leukemogenic fusion proteins are transcriptional repressors that form stable complexes with corepressors, histone deacetylases and histone methyltransferases. Thus, transcriptional repression and gene silencing through RUNX1 contribute to the mechanisms of leukemogenesis of the fusion proteins. Therapies directed at the associated cofactors may be beneficial for treatment of these leukemias.
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PMID:Role of RUNX family members in transcriptional repression and gene silencing. 1515 76

Bone marrow samples from 43 adult patients with de novo diagnosed acute myeloid leukemia (AML)--10 acute promyelocytic leukemias (APL) with t(15;17), four AML with inv(16), seven monocytic leukemias and 22 nonmonocytic leukemias--were analyzed using high-density oligonucleotide microarrays. Hierarchical clustering analysis segregated APL, AML with inv(16), monocytic leukemias and the remaining AML into separate groups. A set of only 21 genes was able to assign AML to one of these three classes: APL, inv(16) and other AML subtype without a specific translocation. Quantitative RT-PCR performed for 18 out of these predictor genes confirmed microarray results. APL expressed high levels of FGF13 and FGFR1 as well as two potent angiogenic factors, HGF and VEGF. AML with inv(16) showed an upregulation of MYH11 and a downregulation of a gene encoding a core-binding factor protein, RUNX3. Genes involved in cell adhesion represented the most altered functional category in monocytic leukemias. Two major groups emerged from the remaining 22 AML: cluster A with 10 samples and cluster B with 12. All the eight leukemias that were either refractory to treatment or that relapsed afterwards were assigned to cluster B. In the latter cluster, CD34 upregulation and serine proteases downregulation is consistent with a maturation arrest and lack of granulocytic differentiation.
Leukemia 2005 Mar
PMID:Gene expression profile reveals deregulation of genes with relevant functions in the different subclasses of acute myeloid leukemia. 1567 61

The RUNX family members play pivotal roles in normal development and neoplasia. RUNX1 and RUNX2 are essential for hematopoiesis and osteogenesis, respectively, while RUNX3 is involved in neurogenesis, thymopoiesis and functions as a tumor suppressor. Inappropriate levels of RUNX activity are associated with leukemia, autoimmune disease, cleidocranial dysplasia, craniosynostosis and various solid tumors. Therefore, RUNX activity must be tightly regulated to prevent tumorigenesis and maintain normal cell differentiation. Recent work indicates that RUNX activity is controlled by various extracellular signaling pathways, and that phosphorylation, acetylation and ubiquitination are important post-translational modifications of RUNX that affect its stability and activity. Defining the precise roles, these modifications that play in the regulation of RUNX function may reveal not only how the RUNX proteins are regulated but also how they are assembled into other regulatory machineries.
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PMID:Phosphorylation, acetylation and ubiquitination: the molecular basis of RUNX regulation. 1632 52

The kinase inhibitor imatinib mesylate targeting the oncoprotein Bcr-Abl has revolutionized the treatment of chronic myeloid leukemia (CML). However, even though imatinib successfully controls the leukemia in chronic phase, it seems not to be able to cure the disease, potentially necessitating lifelong treatment with the inhibitor under constant risk of relapse. On a molecular level, the cause of disease persistence is not well understood. Initial studies implied that innate features of primitive progenitor cancer stem cells may be responsible for the phenomenon. Here, we describe an assay using retroviral insertional mutagenesis (RIM) to identify genes contributing to disease persistence in vivo. We transplanted mice with bone marrow cells retrovirally infected with the Bcr-Abl oncogene and subsequently treated the animals with imatinib to select for leukemic cells in which the proviral integration had affected genes modulating the imatinib response. Southern blot analysis demonstrated clonal outgrowth of cells carrying similar integration sites. Candidate genes located near the proviral insertion sites were identified, among them the transcription factor RUNX3. Proviral integration near the RUNX3 promoter induced RUNX3 expression, and Bcr-Abl-positive cell lines with stable or inducible expression of RUNX1 or RUNX3 were protected from imatinib-induced apoptosis. Furthermore, imatinib treatment selected for RUNX1-expressing cells in vitro and in vivo after infection of primary bone marrow cells with Bcr-Abl and RUNX1. Our results demonstrate the utility of RIM for probing molecular modulators of targeted therapies and suggest a role for members of the RUNX transcription factor family in disease persistence in CML patients.
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PMID:Retroviral insertional mutagenesis identifies RUNX genes involved in chronic myeloid leukemia disease persistence under imatinib treatment. 1736 May 69

Mouse embryonal carcinoma (EC) cells, also called teratocarcinoma stem cells, are nonpermissive for polyomavirus growth, whereas differentiated derivatives of the cells are permissive. Mutant viruses capable of growing in EC cells can be isolated. They have genomic alterations within the viral enhancer, which is required for viral gene expression and DNA replication. This viral regulatory region was considered as a potential probe for mouse cell differentiation. The 24-bp-long A element within the enhancer was identified as a minimum element, which also shows a lower activity in EC cells compared with the differentiated cells. Transcription factors PEA1/AP1, PEA2/PEBP2, and PEA3/ETS were identified as A element-binding proteins. All of them are absent in EC cells and induced to be expressed when the cells are differentiated. Although PEBP2 has a weaker transactivation activity compared with other two, it is essential for the enhancer function of the A element. Purification and cDNA cloning revealed that PEBP2 has two subunits, DNA-binding alpha (PEBP2alpha) and non-DNA-binding beta (PEBP2beta). PEBP2alpha was found to be highly homologous to a Drosophila segmentation gene, runt, and a human gene AML1 that was identified as a part of the fusion gene, AML1/ETO (MTG8) generated by t(8;21) chromosome translocation associated with acute myelogenous leukemia (AML). Core-binding factor (CBF), which interacts with a murine retrovirus enhancer, was found to be identical to PEBP2. runt, PEBP2alpha and AML1 are now termed RUNX family, which are involved in cell specification during development. There are three mammalian RUNX genes, RUNX1, RUNX2, and RUNX3. RUNX1 is essential for generation of hematopoietic stem cells and is involved in human leukemia. RUNX2 is essential for skeletal development and has an oncogenic potential. RUNX3 is expressed in wider ranges of tissues and has multiple roles. Among others, RUNX3 is a major tumor suppressor of gastric and many other solid tumors.
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PMID:RUNX genes in development and cancer: regulation of viral gene expression and the discovery of RUNX family genes. 1803 6

Minimally differentiated acute myeloid leukemia (AML-M0) is defined by immature morphology and expression of early hematologic markers. By gene expression profiling (GEP) and subsequent unsupervised analysis of 35 AML-M0 samples and 253 previously reported AML cases, we demonstrate that AML-M0 cases express a unique signature that is largely separated from other molecular subtypes. Hematologic transcription regulators such as CEBPA, CEBPD, and ETV6, and the differentiation associated gene MPO appeared strongly down-regulated, in line with the primitive state of this leukemia. AML-M0 frequently carries loss-of-function RUNX1 mutation. Unsupervised analyses revealed a subdivision between AML-M0 cases with and without RUNX1 mutations. RUNX1 mutant AML-M0 samples showed a distinct up-regulation of B cell-related genes such as members of the B-cell receptor complex, transcription regulators RUNX3, ETS2, IRF8, or PRDM1, and major histocompatibility complex class II genes. Importantly, prediction with high accuracy of the AML-M0 subtype and prediction of patients carrying RUNX1 mutation within this subtype were possible based on the expression level of only a few transcripts. We propose that RUNX1 mutations in this AML subgroup cause lineage infidelity, leading to aberrant coexpression of myeloid and B-lymphoid genes. Furthermore, our results imply that AML-M0, although originally determined by morphology, constitutes a leukemia subgroup.
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PMID:Gene expression profiling of minimally differentiated acute myeloid leukemia: M0 is a distinct entity subdivided by RUNX1 mutation status. 1966 67

This perspective on RUNX genes discusses their basic biological features, including their DNA-binding alpha subunit, their non-DNA binding beta subunit, and their Runt domain. The evolution of Runx genes begins with one most like Runx3 in invertebrates, progresses to four genes in Drosophila, and to three in vertebrates. Runx genes have two promoters and various numbers of exons and isoforms. All three genes with expressions in the same biological tissues act either synergistically or at different time periods. Runx genes have downstream target genes. Furthermore, Runx genes are mediated by TGFbeta or BMP pathways. They also have cohesin-dependent regulation. Runx1 binds the CD4 silencer and represses transcription in immature double negative thymocytes. Runx1 also activates CD8 as the double negative population progresses to double positive thymocytes. Runx3 establishes epigenetic silencing in CD4 - CD8+ cytotoxic T-cells by binding the CD4 silencer core sequence. Runx1 may also be involved in CD4 silencing in CD8+ T-cells. RUNX1 mutations cause familial thrombocytopenia with a propensity for developing acute myelogenous leukemia; two functional consequences of these mutations include haploinsufficiency and a dominant negative effect. The latter tends to be associated with a higher frequency of leukemia. RUNX2 mutations cause cleidocranial dysplasia; most are of the missense type and commonly occur in the Runt domain. RUNX3 is a tumor suppressor gene with hemizygous deletion of one allele and hypermethylation of the other, resulting in gastric adenocarcinoma.
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PMID:Perspectives on RUNX genes: an update. 1983 Aug 29

Nuclear localization of non-phosphorylated, active beta-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total beta-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated beta-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML.
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PMID:Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation. 2079 89


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