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)

Denileukin diftitox, a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin-2 (IL-2), efficiently targets lymphoma cells expressing the high-affinity IL-2 receptor (IL-2R) consisting of the alpha/p55/CD25, beta/p75/CD122, and gamma/p64/CD132 chains. In vitro studies demonstrated that the retinoid X receptor (RXR) retinoid, bexarotene, at biologically relevant concentrations of 10(-6) M to 10(-8) M, upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox. To determine whether this biomodulatory effect could be recapitulated in vivo, we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene (75 mg/day-300 mg/day) and denileukin diftitox (18 mcg/kg per day x 3 days every 21 days) in a phase 1 trial. Overall response was 67% (4 complete responses, 4 partial responses). Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day. Four patients experienced grade 2 or 3 leukopenia, and 2 had grade 4 lymphopenia. Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses (150 mg/day) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells.
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PMID:A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. 1581 59

We mapped 226 unique integration sites in human hepatoma cells following gene transfer with a feline immunodeficiency virus (FIV)-based lentivirus vector. FIV integrated across the entire length of the transcriptional units. Microarray data indicated that FIV integration favored actively transcribed genes. Approximately 21% of FIV integrations within transcriptional units occurred in genes regulated by the LEDGF/p75 transcriptional coactivator. DNA in regions of FIV insertion sites exhibited a "bendable" structure and a pattern of duplex destabilization favoring strand separation. FIV integration preferences are more similar to those of primate lentiviruses and distinct from those of Moloney murine leukemia virus, avian sarcoma leukosis virus, and foamy virus.
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PMID:Integration site choice of a feline immunodeficiency virus vector. 1691 28

The progressive spongiform encephalomyelopathy caused by ts1, a neuropathogenic temperature-sensitive mutant of Moloney murine leukemia virus (MoMuLV-ts1), results in motor neuronal loss without direct neuronal infection. We have previously reported that ts1-mediated neuronal degeneration in mice has a multifactorial pathogenesis. Here, we report that in the ts1-infected central nervous system (CNS) activated neural cells showed intense immunoreactivity for pro-nerve growth factor (proNGF), neurotrophin receptor p75 (p75(NTR)), and sortilin in the areas showing spongiform changes. Since recent studies suggested that proNGF is more active than mature NGF in inducing neuronal death after binding to co-receptors p75(NTR)/sortilin, we hypothesized that overexpression of proNGF, sortilin and p75(NTR) play a role in ts1-induced neurodegeneration. We found that proNGF and p75(NTR), but not sortilin, mRNA and protein were significantly elevated in ts1-infected brainstem compared to non-infected control tissue. There was extensive tyrosine phosphorylation of p75(NTR), a marker for its activation, in ts1-infected brainstem with abundance in degenerating neurons. We explored whether the increase in the in vivo proNGF expression also occurs in cultured immortalized C1 astrocytes infected by ts1 virus. The proNGF level was significantly increased in infected C1 cells compared to control cells only after addition of fibroblast growth factor (FGF-1). We also showed increased expression of FGF-1 in the CNS of ts1-infected mice. Our findings suggest that the FGF-1 signaling pathway may be responsible for the overexpression of proNGF in neural cells during pathogenesis of ts1-induced neurodegeneration. This study provides new in vivo insights into the possible role of proNGF and its receptors in ts1-induced neurodegeneration.
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PMID:Up-regulation of pro-nerve growth factor, neurotrophin receptor p75, and sortilin is associated with retrovirus-induced spongiform encephalomyelopathy. 1839 88

Overexpression of multidrug resistance proteins (Mdrs) and enhanced antiapoptotic capability are two of the main mechanisms by which Bcr/Abl(+) chronic myeloid leukemia cells acquire drug resistance; however, it has been shown that Mdr-1 expression provides minimal protection against cell apoptosis induced by chemotherapeutic drugs. The mechanism by which cells acquire an enhanced antiapoptosis capacity in the drug-resistant process needs to be further understood. Here, we identified human brain expressed X-linked 1 (hBex1) as a downstream target of the p75 neurotrophin receptor pathway in imatinib-resistant K562 cells by comparing the gene expression profiles with the parent K562 cells. Silencing hBex1 inhibited imatinib-induced cell apoptosis and overexpression of hBex1-sensitized cells to imatinib-induced apoptosis. Further investigation revealed that hBex1 associates with protocadherin 10 (PCDH10). Silencing of pcdh10 attenuated apoptosis induced by imatinib in hBex1 transfected cells, suggesting that, in addition to Mdr and Bcl-2 family members, reduced expression of hBex1 can also inhibit imatinib-induced apoptosis. These data provide evidence that expression of hBex1 in leukemic cells is a novel mechanism by which chemoresistance is achieved and suggests that hBex1 is a potential molecular target for the development of novel leukemia treatments.
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PMID:Inhibition of apoptosis by downregulation of hBex1, a novel mechanism, contributes to the chemoresistance of Bcr/Abl+ leukemic cells. 1902 1

Significant advances have transpired in the human immunodeficiency virus type 1 (HIV-1) integration field in recent years. Considering its essential nature, integrase has long been a target of interest for antiviral drug development. The most significant advance was the approval of the Merck compound raltegravir, the first licensed integrase inhibitor, in October 2007. Another milestone was the identification and characterization of specific nucleoprotein complexes that mediate integrase 3' processing and DNA strand transfer activities in vitro. Genome-wide distribution analyses have furthermore revealed that different retroviruses differentially target distinctive regions of chromatin during integration. For examples, lentiviruses favor actively transcribed genes whereas gammaretroviruses such as Moloney murine leukemia virus prefer transcriptional start sites. Though the underlying mechanisms are unknown for most retroviruses, the lentiviral preference is in large part guided through the interaction with the integrase binding protein lens epithelium-derived growth factor (LEDGF)/p75. Experimental methods that formed the foundations for each of these advances, as well as other techniques topical to the study of HIV-1 integration, are described in this issue of Methods.
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PMID:Mechanistic and pharmacological analyses of HIV-1 integration. 1938 10

Lens epithelium-derived growth factor/p75 (LEDGF/p75) is a transcriptional coactivator involved in stress response, autoimmune disease, cancer and HIV replication. A fusion between the nuclear pore protein NUP98 and LEDGF/p75 has been found in human acute and chronic myeloid leukemia and association of LEDGF/p75 with mixed-lineage leukemia (MLL)/menin is critical for leukemic transformation. During lentiviral replication, LEDGF/p75 tethers the pre-integration complex to the host chromatin resulting in a bias of integration into active transcription units (TUs). The consensus function of LEDGF/p75 is tethering of cargos to chromatin. In this regard, we determined the LEDGF/p75 chromatin binding profile. To this purpose, we used DamID technology and focused on the highly annotated ENCODE (Encyclopedia of DNA Elements) regions. LEDGF/p75 primarily binds downstream of the transcription start site of active TUs in agreement with the enrichment of HIV-1 integration sites at these locations. We show that LEDGF/p75 binding is not restricted to stress response elements in the genome, and correlation analysis with more than 200 genomic features revealed an association with active chromatin markers, such as H3 and H4 acetylation, H3K4 monomethylation and RNA polymerase II binding. Interestingly, some associations did not correlate with HIV-1 integration indicating that not all LEDGF/p75 complexes on the chromosome are amenable to HIV-1 integration.
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PMID:High-resolution profiling of the LEDGF/p75 chromatin interaction in the ENCODE region. 2048 70

PSIP1 (PC4 and SFRS1 interacting protein 1) encodes two splice variants: lens epithelium-derived growth factor or p75 (LEDGF/p75) and p52. PSIP1 gene products were shown to be involved in transcriptional regulation, affecting a plethora of cellular processes, including cell proliferation, cell survival, and stress response. Furthermore, LEDGF/p75 has implications for various diseases and infections, including autoimmunity, leukemia, embryo development, psoriasis, and human immunodeficiency virus integration. Here, we reported the first characterization of the PSIP1 promoter. Using 5' RNA ligase-mediated rapid amplification of cDNA ends, we identified novel transcription start sites in different cell types. Using a luciferase reporter system, we identified regulatory elements controlling the expression of LEDGF/p75 and p52. These include (i) minimal promoters (-112/+59 and +609/+781) that drive the basal expression of LEDGF/p75 and of the shorter splice variant p52, respectively; (ii) a sequence (+319/+397) that may control the ratio of LEDGF/p75 expression to p52 expression; and (iii) a strong enhancer (-320/-207) implicated in the modulation of LEDGF/p75 transcriptional activity. Computational, biochemical, and genetic approaches enabled us to identify the transcription factor Sp1 as a key modulator of the PSIP1 promoter, controlling LEDGF/p75 transcription through two binding sites at -72/-64 and -46/-36. Overall, our results provide initial data concerning LEDGF/p75 promoter regulation, giving new insights to further understand its biological function and opening the door for new therapeutic strategies in which LEDGF/p75 is involved.
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PMID:LEDGF/p75 TATA-less promoter is driven by the transcription factor Sp1. 2201 92

Recent studies of mammalian genomes suggest that alternative promoters are associated with various disorders, including cancer. Here we present an intronic promoter of the murine proteinase 3 gene, which drives the expression of an alternative mRNA in intron 2 of the prtn3 gene. The proximal promoter sequences were identified and a series of promoter deletion constructs were used to identify the sequence elements that are required for basal promoter activity. Expression of the homeobox transcription factor CUX1 p75 isoform was found to suppress the activity of the alternative PR3 promoter. Data base analyses, multiple alignments and expression data showed that the intronic PR3 promoter is active in leukemia and other tumor cells as well as in mouse embryo, male mammary gland and bone marrow. In the spleen, the transcript is exclusively expressed by Gr-1(int) /CD11b(+) cells, which are also known as myeloid-derived suppressor cells (MDSCs). In humans, an alternative transcript of the PR3-gene could be detected in the bone marrow and in various cancer cell lines but not in primary leukemia cells, suggesting a species-overarching function of this kind of promoter. Therefore, the alternative PR3 promoter and its mRNA may be useful tools to investigate the fate of hematopoietic stem cells.
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PMID:Intronic promoters and their noncoding transcripts: a new source of cancer-associated genes. 2293 Mar 95

The lens epithelium-derived growth factor (LEDGF/p75) tethers the mixed-lineage leukemia (MLL1) protein complex to chromatin. Likewise, LEDGF/p75 tethers the HIV-1 pre-integration complex to chromatin. We previously demonstrated that expression of the C-terminal fragment fused to enhanced green fluorescent protein (eGFP) (eGFP-LEDGF(325-530)) impaired HIV-1 replication. Here, we explored this strategy to selectively interfere with the leukemogenic activity of MLL-fusion proteins. We found that expression of LEDGF(325-530) impaired the clonogenic growth of MLL-fusion gene transformed human and mouse hematopoietic cells, without affecting the growth of control cells immortalized by the FLT3-ITD mutant or normal lineage-marker-depleted murine bone marrow cells. Expression of LEDGF(325-530) was associated with downregulation of the MLL target Hoxa9 and impaired cell cycle progression. Structure-function analysis revealed two small eGFP-fused LEDGF/p75 peptides, LEDGF(424-435) and LEDGF(375-386) phenocopying these effects. Both LEDGF(325-530) and the smaller active peptides were able to disrupt the LEDGF/p75-MLL interaction. Expression of LEDGF(325-530) or LEDGF(375-386) fragments increased the latency period to disease development in vivo in a mouse bone marrow transplant model of MLL-AF9-induced AML. We conclude that small peptides disrupting the LEDGF/p75-MLL interface have selective anti-leukemic activity providing a direct rationale for the design of small molecule inhibitors targeting this interaction.
Leukemia 2013 Jun
PMID:Impairing MLL-fusion gene-mediated transformation by dissecting critical interactions with the lens epithelium-derived growth factor (LEDGF/p75). 2331 60

A hallmark of retroviral replication is integration of the viral genome into host cell DNA. This characteristic makes retrovirus-based vectors attractive delivery vehicles for gene therapy. However, adverse events in gene therapeutic trials, caused by activation of proto-oncogenes due to murine leukemia virus (MLV)-derived vector integration, hamper their application. Here, we show that bromodomain and extraterminal (BET) proteins (BRD2, BRD3, and BRD4) and MLV integrase specifically interact and colocalize within the nucleus of the cell. Inhibition of the BET proteins' chromatin interaction via specific bromodomain inhibitors blocks MLV virus replication at the integration step. MLV integration site distribution parallels the chromatin binding profile of BET proteins, and expression of an artificial fusion protein of the BET integrase binding domain with the chromatin interaction domain of the lentiviral targeting factor LEDGF/p75 retargets MLV integration away from transcription start sites and into the body of actively transcribed genes, conforming to the HIV integration pattern. Together, these data validate BET proteins as MLV integration targeting factors.
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PMID:The BET family of proteins targets moloney murine leukemia virus integration near transcription start sites. 2418 73


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