Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TLS-ERG fusion protein is derived from the t(16;21) translocation found in human myeloid leukemia. Here, we show that retroviral transduction of TLS-ERG confers a growth advantage to L-G myeloid progenitor cells and blocks terminal differentiation. We found that the level of cyclin-dependent kinase 1 (Cdk1) protein was significantly decreased in controls but unchanged in TLS-ERG-expressing cells after granulocyte colony-stimulating factor treatment or interleukin-3 withdrawal. Injection of TLS-ERG-expressing L-G cells induced rapid development of a leukemia-like disease in syngeneic mice. Through site-directed mutagenesis, we showed that transformation and deregulation of Cdk1 by TLS-ERG require an intact ets DNA-binding domain within the fusion protein. Interestingly, treatment of TLS-ERG-expressing L-G cells with 5-aza-2'-deoxycytidine (Decitabine) or trichostatin A resulted in down-regulation of Cdk1 and induction of terminal differentiation. To investigate whether Cdk1 deregulation is indeed responsible for transformation by TLS-ERG, we constructed lentiviral vectors for delivery of Cdk1 mutants and small interfering RNA (siRNA). Both dominant-negative inhibition and siRNA knockdown of Cdk1 were able to restore the ability of TLS-ERG-expressing L-G cells to undergo terminal differentiation. In addition, siRNA knockdown of Cdk1 in YNH-1 cells derived from a t(16;21) acute myelogenous leukemia patient also resulted in terminal differentiation. As restoration of terminal myeloid differentiation to TLS-ERG cells is dependent on cell cycle arrest, our findings suggest an important role for Cdk1 in cellular transformation and may be useful in the search for new treatments of TLS-ERG-associated myeloid leukemia.
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PMID:TLS-ERG leukemia fusion protein deregulates cyclin-dependent kinase 1 and blocks terminal differentiation of myeloid progenitor cells. 1850 30

(E)-4-[3-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure-anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3'-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.
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PMID:Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and inhibition of SRC homology 2 domain-containing protein tyrosine phosphatase-2 activity. 1875 24

The 8;21 translocation, which involves the gene encoding the RUNX family DNA-binding transcription factor AML1 (RUNX1) on chromosome 21 and the ETO (MTG8) gene on chromosome 8, generates AML1-ETO fusion proteins. Previous analyses have demonstrated that full-length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. More recently, we have identified an alternatively spliced form of AML1-ETO, AML1-ETO9a, from t(8;21) acute myeloid leukemia (AML) patient samples. AML1-ETO9a lacks the C-terminal NHR3 and NHR4 domains of AML1-ETO and is highly leukemogenic in the mouse model. Here, we report that the AML1 DNA-binding domain and the ETO NHR2-dimerization domain, but not the ETO NHR1 domain, are critical for the induction of AML by AML1-ETO9a. A region between NHR1 and NHR2 affects latency of leukemogenesis. These results provide valuable insight into further analysis of the molecular mechanism of t(8;21) in leukemogenesis.
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PMID:RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis. 1903 4

Small heterodimer partner (SHP) is an atypical member of nuclear receptor superfamily that lacks a DNA-binding domain. In previous study, we showed that SHP, c-jun, p65 of NF-gammaB subunits, and p21WAF1 expression was increased during monocytic differentiaton with the exposure of human leukemia cells to a differentiation agent, PMA. In this study, c-Jun and p65 were shown to mediate the transcriptional activation of the SHP promoter. In addition, SHP induced the cell cycle regulatory protein levels and cooperatively increased an induction of p21WAF1 expression with p65. Furthermore, SHP protected differentiated cells from etoposide-induced cellular apoptosis through the induction and cytoplasmic sequestration of p21WAF1. Complex formation between SHP and p21WAF1 was demonstrated by means of coimmunoprecipitation. These results suggest that SHP prolongs a cellular survival of differentiating monocytes through the transcriptional regulation of target genes of cell survival and differentiation.
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PMID:The orphan nuclear receptor SHP inhibits apoptosis during the monocytic differentiation by inducing p21WAF1. 1932 21

The t(8:21)(q22;q22) translocation is 1 of the most common chromosomal abnormalities linked to acute myeloid leukemia (AML). AML1-ETO, the product of this translocation, fuses the N-terminal portion of the RUNX transcription factor AML1 (also known as RUNX1), including its DNA-binding domain, to the almost entire transcriptional corepressor ETO (also known as MTG8 or RUNX1T1). This fusion protein acts primarily by interfering with endogenous AML1 function during myeloid differentiation, although relatively few genes are known that participate with AML1-ETO during leukemia progression. Here, we assessed the consequences of expressing this chimera in Drosophila blood cells. Reminiscent of what is observed in AML, AML1-ETO specifically inhibited the differentiation of the blood cell lineage whose development depends on the RUNX factor Lozenge (LZ) and induced increased numbers of LZ(+) progenitors. Using an in vivo RNAi-based screen for suppressors of AML1-ETO, we identified calpainB as required for AML1-ETO-induced blood cell disorders in Drosophila. Remarkably, calpain inhibition triggered AML1-ETO degradation and impaired the clonogenic potential of the human t(8;21) leukemic blood cell line Kasumi-1. Therefore Drosophila provides a promising genetically tractable model to investigate the conserved basis of leukemogenesis and to open avenues in AML therapy.
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PMID:A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO. 1958 87

The c-myb proto-oncogene is a key regulator of hematopoietic cell proliferation and differentiation. MYB mRNA is expressed at high levels in, and is required for the proliferation of, most human myeloid and acute lymphoid leukemias. Recently, chromosomal translocation and genomic duplications of c-MYB have been identified in human T-cell acute leukemia. The present work focuses on the effects of mutations in different domains of the murine c-Myb protein on its transforming ability as defined by suppression of myelomonocytic differentiation and continued proliferation. Using both a novel myeloid cell line-based assay and a primary hematopoietic cell assay, we have shown that mutation of single residues in the transactivation domain important for CBP/p300 binding leads to complete loss of transforming ability. We also simultaneously mutated residues in the DNA-binding domain and the negative regulatory domain of the protein. These double mutants, but not the corresponding single mutants, show a complete loss of transforming activity. Surprisingly, these double mutants show severely impaired transactivation and are also defective for CBP/p300 binding. Our results imply that multiple Myb domains influence its interaction with CBP/p300, highlight the importance of this interaction for myeloid transformation, and suggest an approach for molecular targeting of Myb in leukemia.
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PMID:Mutations in multiple domains of c-Myb disrupt interaction with CBP/p300 and abrogate myeloid transforming ability. 1973 67

Reciprocal t(16;21)(p11;q22) is a rare chromosomal abnormality in acute myeloid leukemia (AML). The chimeric transcript FUS-ERG formed by this translocation which causes the replacement of RNA-binding domain of FUS (alias TLS) with the DNA-binding domain of ERG, and this event is thought to be responsible for leukemogenesis. Here we report two cases of AML with t(16;21)(p11.2;q22) showing unusual characteristics, and address the clinical, hematological, and molecular aspects of leukemia with t(16;21), along with a review of the literature.
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PMID:Detection of FUS-ERG chimeric transcript in two cases of acute myeloid leukemia with t(16;21)(p11.2;q22) with unusual characteristics. 1978 43

Ets-1 is a transcription factor that plays an important role in various physiological and pathological processes, such as development, angiogenesis, apoptosis and tumour invasion. In the present study, we have demonstrated that Ets-1 p51, but not the spliced variant Ets-1 p42, is processed in a caspase-dependent manner in Jurkat T-leukaemia cells undergoing apoptosis, resulting in three C-terminal fragments Cp20, Cp17 and Cp14 and a N-terminal fragment, Np36. In vitro cleavage of Ets-1 p51 by caspase 3 produces fragments consistent with those observed in cells undergoing apoptosis. These fragments are generated by cleavage at three sites located in the exon VII-encoded region of Ets-1 p51. This region is absent from the Ets-1 p42 isoform, which therefore cannot be cleaved by caspases. In Ets-1 p51, cleavage generates C-terminal fragments containing the DNA-binding domain, but lacking the transactivation domain. The Cp17 fragment, the major cleavage product generated during apoptosis, is devoid of transcriptional activity and inhibits Ets-1 p51-mediated transactivation of target genes by competing with Ets-1 p51 for binding to Ets-binding sites present in the target promoters. In the present study, we have demonstrated that caspase cleavage of Ets-1 within the exon VII-encoded region leads to specific down-regulation of the Ets-1 p51 isoform during apoptosis. Furthermore, our results establish that caspase cleavage generates a stable C-terminal fragment that acts as a natural dominant-negative form of the full-length Ets-1 p51 protein.
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PMID:Caspase cleavage of Ets-1 p51 generates fragments with transcriptional dominant-negative function. 2000 63

Gene regulatory networks in living cells are controlled by the interaction of multiple cell type-specific transcription regulators with DNA binding sites in target genes. Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence binding protein (ICSBP), is a transcription factor expressed predominantly in myeloid and lymphoid cell lineages. To find the functional direct target genes of IRF8, the gene expression profiles of siRNA knockdown samples and genome-wide binding locations by ChIP-chip were analyzed in THP-1 myelomonocytic leukemia cells. Consequently, 84 genes were identified as functional direct targets. The ETS family transcription factor PU.1, also known as SPI1, binds to IRF8 and regulates basal transcription in macrophages. Using the same approach, we identified 53 direct target genes of PU.1; these overlapped with 19 IRF8 targets. These 19 genes included key molecules of IFN signaling such as OAS1 and IRF9, but excluded other IFN-related genes amongst the IRF8 functional direct target genes. We suggest that IRF8 and PU.1 can have both combined, and independent actions on different promoters in myeloid cells.
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PMID:The combination of gene perturbation assay and ChIP-chip reveals functional direct target genes for IRF8 in THP-1 cells. 2057 2

Retroviral vectors offer benefits of efficient delivery and stable gene expression; however, their clinical use raises the concerns of insertional mutagenesis and potential oncogenesis due to genomic integration preferences in transcriptional start sites (TSS). We have shifted the integration preferences of retroviral vectors by generating a library of viral variants with a DNA-binding domain inserted at random positions throughout murine leukemia virus Gag-Pol, then selecting for variants that are viable and exhibit altered integration properties. We found seven permissive zinc finger domain (ZFD) insertion sites throughout Gag-Pol, including within p12, reverse transcriptase, and integrase. Comprehensive genome integration analysis showed that several ZFD insertions yielded retroviral vector variants with shifted integration patterns that did not favor TSS. Furthermore, integration site analysis revealed selective integration for numerous mutants. For example, two retroviral variants with a given ZFD at appropriate positions in Gag-Pol strikingly integrated primarily into four common sites out of 3.1 x 10(9) possible human genome locations (P = 4.6 x 10(-29)). Our findings demonstrate that insertion of DNA-binding motifs into multiple locations in Gag-Pol can make considerable progress toward engineering safer retroviral vectors that integrate into a significantly narrowed pool of sites on human genome and overcome the preference for TSS.
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PMID:Specific insertions of zinc finger domains into Gag-Pol yield engineered retroviral vectors with selective integration properties. 2061 52


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