Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mithramycin induces a reversible inhibition of cellular RNA synthesis without affecting DNA synthesis. The authors have shown this drug induces myeloid differentiation of HL-60 promyelocytic leukemia cells and is an effective agent in certain patients with chronic granulocytic leukemia. In order to investigate the mechanism by which this drug inhibits RNA synthesis we have compared the effect of mithramycin on RNA synthesis by whole cells, isolated nuclei, and RNA synthesis by isolated E. coli RNA polymerase and eukaryotic RNA polymerase II. Exposure of HL-60 cells to mithramycin at concentrations of 4.6 X 10(-7) m or higher for 48 hours causes an almost immediate inhibition of RNA synthesis (up to 85% at 4 hours) with only modest cytotoxicity at these concentrations. Endogenous RNA synthesis by isolated nuclei can be inhibited by mithramycin only at high concentrations (greater than 10(-5) m), suggesting that mithramycin primarily may inhibit initiation, rather than elongation. Mithramycin inhibits in vitro transcription of salmon sperm DNA by E. coli RNA polymerase at DNA:drug ratios similar to those required for RNA synthesis inhibition in whole cells. Similar DNA binding studies with synthetic oligonucleotides demonstrate that mithramycin is a potent inhibitor of transcription of Poly dG.dC by E. coli RNA polymerase but has no effect on transcription of Poly dA.dT. The rapid inhibition of whole cell and isolated RNA polymerase transcription, and the relative insensitivity of isolated nuclei, suggest mithramycin may interact with specific DNA sequences in order to inhibit the initiation of RNA synthesis in intact cells.
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PMID:Mithramycin selectively inhibits transcription of G-C containing DNA. 296 90

Ribozymes have been developed to cleave the bcr-abl transcripts and thereby suppress transforming activities of chronic myelogenous leukemia (CML) cells. However, the intracellular efficacy of vector-dependent ribozymes usually depends in part on their expression cassettes, which may affect their intracellular trafficking and distribution. In order to test effects of an intron in pre-fusion ribozyme on the anti-bcr-abl activities in CML cells, retroviral vectors harboring ribozyme expression cassettes with (RzI) or without (Rz) an intron-encoding sequence were used to transduce K562 cells. In terms of both reduction of the target bcr-abl mRNA and suppression of colony formation in soft agar and xenograft growth on SCID mice, the anti-bcr-abl efficacy of the RzI fusion ribozyme was significantly superior to that of Rz. These results also correlate with more cytoplasmic accumulation of the RzI fusion ribozymes than that of the Rz. This study suggests activities of a RNA polymerase II-driven fusion ribozyme against its targeted spliced mRNA are improved by incorporating an intron in its pre-splicing transcript. Noticeably, the improvement is contributed in part by subcellular co-localization.
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PMID:An intron promotes the anti-bcr-abl activities of a retrovirally expressed ribozyme in chronic myeloid leukemia cells. 1514 4

Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Abl fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Abl kinase inhibitor imatinib against chronic-phase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Abl protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Abl-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II-directed mRNA synthesis, and decreased the Bcr-Abl transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Abl protein level. Imatinib directly inhibited the kinase activity of Bcr-Abl. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Abl were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors.
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PMID:A sequential blockade strategy for the design of combination therapies to overcome oncogene addiction in chronic myelogenous leukemia. 1710 34

Imatinib (STI571) is the frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML). However, resistance to imatinib due to point mutations in Bcr-Abl kinase domain is an emerging problem. We recently reported that triptolide (compound 1) could effectively kill CML cells including those harboring T315I mutant Bcr-Abl. In the present study, we designed a series of C-14 triptolide derivatives with C-14-hydroxyl substituted by different amine esters (3-18): 3-6 and 13 (by aliphatic chain amine esters); 7-9, 11, 12 and 15-18 (by alicyclic amine esters with different size), and 10 and 14 (by aralkylamine esters).The compounds were examined for their antineoplastic activity against CML cells (including KBM5-T315I cells) in terms of proliferation inhibition, apoptosis and signal transduction. Nude mouse xenograft model was also used to evaluate the in vivo activity. Compounds 2-9, 11-14, 17 and 18 exhibited a potent inhibitory activity against KBM5 and KBM5-T315I cells. This series of derivatives down-regulated Bcr-Abl mRNA. Compounds 4, 5, 8 and 9 were further examined for their impact on signaling and apoptosis with immunoblotting. Compound 5 was chosen for evaluation in a nude mouse xenograft model. The stereo-hindrance of C-14 group appeared to be responsible for the antitumor effect. The computational small molecule-protein docking analysis illustrated the possible interaction between compound 9 and RNA polymerase II. Our results suggest that this series of derivatives may be promising agents to overcome imatinib-resistance caused by the Bcr-Abl-T315I mutation.
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PMID:Design, synthesis, and biological evaluation of novel water-soluble triptolide derivatives: Antineoplastic activity against imatinib-resistant CML cells bearing T315I mutant Bcr-Abl. 2014 65

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

The human K562 chronic myeloid leukemia cell line has long served as an experimental paradigm for functional genomic studies. To systematically and functionally annotate the human genome, the ENCODE consortium generated hundreds of functional genomic data sets, such as chromatin immunoprecipitation coupled to sequencing (ChIP-seq). While ChIP-seq analyses have provided tremendous insights into gene regulation, spatiotemporal insights were limited by a resolution of several hundred base pairs. ChIP-exonuclease (ChIP-exo) is a refined version of ChIP-seq that overcomes this limitation by providing higher precision mapping of protein-DNA interactions. To study the interplay of transcription initiation and chromatin, we profiled the genome-wide locations for RNA polymerase II (Pol II), the histone variant H2A.Z, and the histone modification H3K4me3 using ChIP-seq and ChIP-exo. In this Data Descriptor, we present detailed information on parallel experimental design, data generation, quality control analysis, and data validation. We discuss how these data lay the foundation for future analysis to understand the relationship between the occupancy of Pol II and nucleosome positions at near base pair resolution.
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PMID:ChIP-seq and ChIP-exo profiling of Pol II, H2A.Z, and H3K4me3 in human K562 cells. 2950 91

The potential biological relationship between type-2 diabetes mellitus (T2DM) has been focused in numerous studies. To investigate the molecular associations among T2DM, prostate cancer (PCa), and chronic myeloid leukemia (CML), using a biomolecular network enrichment analysis. We obtained a list of disease-related genes and constructed disease networks. Then, GO enrichment analysis was performed to identify the significant functions and pathways of overlapping modules in the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. More than 75% of these overlapping genes were found to be consistent with the findings of previous studies. In the three diseases, we found that Sarcoglycan delta (SGCD) and Rho family GTPase 3 (RND3) were the overlapping genes and identified negative regulation of apoptotic process and negative regulation of transcription from RNA polymerase II promoter RNA as the two overlapping biological functions. CML and PCa were the most closely related, with 34 overlapping genes, five overlapping modules, 27 overlapping biological functions, and nine overlapping pathways. There were 13 overlapping genes, one overlapping modules, four overlapping biological functions and one overlapping pathway (FoxO signaling pathway) were found in T2DM and CML.And T2DM and PCa were the least related pair in our study, with only six overlapping genes, five overlapping modules, and one overlapping biological function. SGCD and RND3 were the main gene-to-gene relationship among T2DM, CML, and PCa; apoptosis, development, and transcription from RNA polymerase II promote processes were the main functional connections among T2DM, CML, and PCa by network enrichment analysis. There is a "scalene" relationship among T2DM, CML, and PCa at gene, pathway, biological process, and module levels: CML and PCa were the most closely related, the second were T2DM and PCa, and T2DM and PCa were the least related pair in our study. Our study provides a new avenue for further studies on T2DM and cancers, which may promote the discovery and development of novel therapeutic and can be used to treat multiple diseases.
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PMID:Deciphering the scalene association among type-2 diabetes mellitus, prostate cancer, and chronic myeloid leukemia via enrichment analysis of disease-gene network. 3093 5

To elucidate dynamic changes in native BCR-ABL and alternatively spliced tyrosine kinase inhibitor (TKI)-resistant but function-dead BCR-ABLIns35bp variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR-ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR-ABLIns35bp , accounting for 0.8% of the total IS BCR-ABL, corresponding to actual BCR-ABLIns35bp value of 1.1539% IS. TKI rapidly decreased native BCR-ABL but not BCR-ABLIns35bp , leading to the initial increase in the proportion of BCR-ABLIns35bp . Thereafter, both native BCR-ABL and BCR-ABLIns35bp gradually decreased in the course of TKI treatment, whereas small populations positive for TKI-resistant BCR-ABLIns35bp continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR-ABL+ clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function-dead BCR-ABLIns35bp , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis-splicing BCR-ABLIns35bp , occurring at the particular pseudo-splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR-ABL extracting BCR-ABLIns35bp would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.
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PMID:Tyrosine kinase inhibitors induce alternative spliced BCR-ABLIns35bp variant via inhibition of RNA polymerase II on genomic BCR-ABL. 3231 54