Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myeloid leukemia (AML) is an intrinsically resistant disease. Prognosis is poor for the majority of AML patients, based on age and/or adverse biologic features. Standard therapy for AML is highly toxic and poorly tolerated, particularly by the group of older patients for whom few useful therapies exist. Allogeneic hematopoietic stem cell transplantation is an important option for patients with high-risk AML during first remission, as well as for any patient in second or subsequent remission. Use of reduced intensity conditioning transplantations has made allogeneic stem cell transplantation available for a wider group of individuals, but the impact of this novel procedure on the natural history of AML is unknown. The major thrust of novel therapeutics in AML is development of so-called targeted therapies, which are based on exploitation of newly understood pathophysiological events critical for leukemogenesis. Such events include unbridled proliferation, failure to differentiate, stromal cell-mediated survival factors, and failure to undergo normal programmed cell death. Therapies developed to deal with these problems include inhibitors of ras physiology and activated tyrosine kinases, such as fms-like tyrosine kinase 3; histone deacetylase inhibitors, and DNA-hypomethylating agents, which promote transcription of silenced genes; angiogenesis inhibitors; and anti-bcl-2 agents, respectively. Challenges in therapeutic development include the likelihood that only a subset of AML patients will respond to any of these therapies, based on the patient's intrinsic pathophysiology as well as the fact that many of these agents will only work in conjunction with chemotherapy or other viable antileukemic therapies.
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PMID:Novel therapeutic agents in acute myeloid leukemia. 1737 2

PU.1 is one of key regulators of hematopoietic cell development, a tightly-regulated lineage-specific process. Here we provide the first evidence that PU.1 protein is cleaved into two fragments of 24 kDa and 16 kDa during apoptosis progression in leukemic cell lines and primary leukemic cells. Further experiments with specific capase-3 inhibitor Z-DEVD-fmk and the in vitro proteolytic system confirmed that PU.1 is a direct target of caspase-3. Using site-directed mutagenesis analyses, the aspartic acid residues at positions 97 and 151 of PU.1 protein were identified as capsase-3 target sites. More intriguingly, the suppression of PU.1 expression by small interfering RNAs (siRNAs) significantly inhibits DNA-damaging agents NSC606985 and etoposide-induced apoptosis in leukemic cells, together with the up-regulated expression of anti-apoptotic bcl-2 gene. These results would provide new insights for understanding the mechanism of PU.1 protein in hematopoiesis and leukemogenesis.
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PMID:PU.1, a novel caspase-3 substrate, partially contributes to chemotherapeutic agents-induced apoptosis in leukemic cells. 1928 94

AML1-ETO fusion protein (AE) is generated by t(8;21)(q22;q22) chromosomal translocation, which is one of the most frequently observed structural abnormalities in acute myeloid leukemia (AML) and displays a pivotal role in leukemogenesis. The histone acetyltransferase p300 promotes self-renewal of leukemia cells by acetylating AE and facilitating its downstream gene expression as a transcriptional coactivator, suggesting that p300 may be a potential therapeutic target for AE-positive AML. However, the effects of p300 inhibitors on leukemia cells and the underlying mechanisms have not been extensively investigated. In the current study, we analyzed the anti-leukemia effects of C646, a selective and competitive p300 inhibitor, on AML cells. Results showed that C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in AE-positive AML cell lines and primary blasts isolated from leukemic mice and AML patients. Nevertheless, no significant inhibitory effects were observed in granulocyte colony-stimulating factor-mobilized normal peripheral blood stem cells. Notably, AE-positive AML cells were more sensitive to lower C646 doses than AE-negative ones. And C646-induced growth inhibition on AE-positive AML cells was associated with reduced global histone H3 acetylation and declined c-kit and bcl-2 levels. Therefore, C646 may be a potential candidate for treating AE-positive AML.
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PMID:A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells. 2339 May 36


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