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)

Histone acetylation is one major mechanism by which chromatin structure and function are regulated. Besides histones, many nonhistone proteins are also acetylated in vivo. Aberrant acetylation has been linked to the development of various human diseases. Through acetylating histone and nonhistone proteins, histone acetyltransferases (HATs) play fundamental roles in regulating chromatin remodeling, transcription, and other nuclear processes. Known HATs belong to several groups, including the GCN5/PCAF, p300/CBP, and MYST families. ESA1, SAS3, MOF, TIP60, HBO1, MOZ, and MORF are the MYST family members with demonstrated HAT activity. The MOZ and MORF genes are rearranged by chromosome abnormalities associated with several types of leukemia, so these two HATs have been implicated in leukemogenesis. Compared with p300, CBP, and PCAF, much less is known about MOZ and MORF. To elucidate the function and regulation of these two interesting HATs, we have conducted their initial characterization. Here we describe the expression, purification, and activity analysis of MOZ and MORF. For comparison, we also include the procedure for expression and purification of PCAF. These methods are useful not only for functional characterization of MOZ, MORF, PCAF, and other HATs, but also for preparation of HAT proteins to screen compound libraries and obtain inhibitors with potential therapeutic value.
 ...
PMID:Expression, purification, and analysis of MOZ and MORF histone acetyltransferases. 1289 70

Treatment with LAQ824 (Novartis Pharmaceutical, Inc.), a cinnamyl hydroxamic acid analogue inhibitor of histone deacetylases, depleted the mRNA and protein expression of Bcr-Abl in human chronic myeloid leukemia blast crisis (CML-BC) cells. Exposure to LAQ824 induced the expression of the cell cycle-dependent kinase inhibitors p21 and p27 and caused cell cycle G(1)-phase accumulation and apoptosis of CML-BC cells. LAQ824 also induced acetylation of heat shock protein 90. This inhibited the chaperone association of Bcr-Abl with heat shock protein 90, thereby promoting the proteasomal degradation of Bcr-Abl. Cotreatment with LAQ824 increased imatinib mesylate-induced apoptosis of CML-BC cells. Additionally, LAQ824 down-regulated the levels of mutant Bcr-Abl possessing the T315I point mutation, as well as induced apoptosis of imatinib-refractory primary CML-BC cells. Therefore, LAQ824 may be a promising therapeutic agent in the treatment of imatinib-sensitive or -refractory human leukemia.
 ...
PMID:Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. 1294 44

The last decade has witnessed a multistep evolution in the understanding of the natural history, clinical manifestations, and some of the molecular mechanisms that underlie the ineffective hematopoiesis and leukemic transformation in the myelodysplastic syndrome (MDS). The international prognostic scoring system, FAB, and WHO classifications have helped define specific subgroups with their characteristic cytogenetic, molecular and immunological abnormalities. Until recently the mainstay of the treatment has been entirely supportive with blood and platelet transfusions. What is increasingly manifest now is the considerable excitement generated by the emergence of novel therapeutic strategies based on painstaking research findings from the laboratories. In Section I, Dr. Alan List reviews the therapeutic strategies with the specific emphasis on the relevance of molecular mechanism of apoptosis and targeted therapies using small molecules. Of particular interest is the excitement surrounding the clinical benefit obtained from potent immunomodulatory derivative (IMiD) of thalidomide CC5013. The review provides an update of the role of small molecule inhibitors of VEGF receptor tyrosine kinase, arsenic trioxide, oral matrix metalloprotease inhibitors, farnesyl transferase inhibitors, and imatinib mesylate in the treatment of MDS subgroups. In Section II, Dr. Steven Gore describes the results of clinical trials of inhibitors of DNA methylation such as 5 azacytidine (5 AC) and 5-aza 2-deoxycytidine (Decitabine). The review also provides an update on the rationale and results obtained from the combination therapy using histone deacetylases (HDAC) and DNA methyltransferase inhibitors in the treatment of MDS. In Section III, Professor Ghulam Mufti and Dr. Aloysius Ho describe the role of bone marrow transplantation with particular emphasis on recent results from reduced-intensity conditioned transplants, exploiting the graft versus leukemia effect without significant early treatment-related mortality. The section provides an update on the results obtained from the manipulation of the host's immune system with immunosuppressive agents such as ALG and/or cyclosporine A.
 ...
PMID:Myelodysplastic syndrome. 1463 82

The WW domain containing oxidoreductase (WWOX) gene was recently identified as a candidate tumor suppressor gene at a common fragile site, FRA16D. Because the fragile histidine triad (FHIT) gene, a tumor suppressor gene encompassing the most active, common fragile site FRA3B, is frequently deleted in various cancers, we evaluated the expression of WWOX and FHIT in 74 cases of primary hematopoietic neoplasias and 20 leukemia cell lines. Aberration or absence of WWOX transcripts was detected in 51% of the primary cases and 55% of cell lines, and three WWOX nucleotide variants were detected among the leukemia cell lines. FHIT expression was absent or altered in 36% of the primary cases and 15% of cell lines. The occurrence of aberrant FHIT reverse transcription-PCR products correlated significantly with the occurrence of WWOX alterations. Wild-type transcripts of both genes were expressed in normal hematopoiesis along with a small fraction of short transcripts. A DNA blot study showed that WWOX and FHIT genes were deleted in 2 of 18 cases with primary acute leukemias; both genes were not expressed in the 2 cases. Furthermore, treatment of cells with a demethylating or histone acetylating agent in culture resulted in increased expression of WWOX and FHIT mRNA in leukemia cells. Conclusions are that WWOX expression is frequently altered or absent in hematopoietic disorders, often in association with FHIT alterations, and that alterations of these fragile genes may result not only from genomic deletions but also from epigenetic modifications associated with expression of fragility.
 ...
PMID:Expression of FRA16D/WWOX and FRA3B/FHIT genes in hematopoietic malignancies. 1463 66

Therapeutic approaches aimed at developing epigenetically-effective drugs are under intense investigation. Several classes of enzymes regulating histone acetylation and DNA methylation, which are required for epigenetic transitions, offer attractive targets for therapeutic interventions. Imbalances in histone acetylation and DNA methylation may play a significant role in the development of cancer and leukaemia and may provide a mechanistic rationale for targeting epigenetic modifications. Clinical trials designed to evaluate inhibitors of DNA methylation and histone deacetylase inhibitors are showing encouraging results in cancer patients. A growing quantity of data from preclinical research supports the notion that epigenetically-effective drugs could also find an application in other therapeutic areas. A number of emerging biomarkers may prove useful for monitoring drug effects and defining molecular signatures of response, toxicity and effective dose.
 ...
PMID:Epigenetic transitions: towards therapeutic targets. 1464 Sep 6

The post-translational modification of the core histones is critical to the regulation of chromatin structure. Traditional methods for the determination of histone modification utilize immunoassay techniques to determine the extent and site of post-translational modification. These methods, though sensitive, require site-specific antibodies. This manuscript describes the application of reverse-phase high-pressure liquid chromatography and mass spectrometry (LC-MS) to analyze global modification levels of core histones. The method is fast, sensitive, and easily automated. Furthermore, the technique gives the global patterns of modification for all four core histones in a single experiment. The LC-MS method was optimized using histones extracted from bovine thymus. These methods were then applied to the characterization of changes in histone modification in acute myeloid leukemia (AML) cell lines treated with histone deacetylase (HDAC) inhibitors. Dose-dependent changes in the distribution of modified core histones were observed. These results were validated in primary leukemia cells from patients with refractory or relapsed AML or chronic lymphocytic leukemia (CLL) treated on a Phase I clinical trial of the HDAC inhibitor depsipeptide. An increase in the relative abundance of specific acetylated forms of histone H4 was readily observable in these patients at intervals of 4 and 24 h after treatment.
 ...
PMID:Differential expression of histone post-translational modifications in acute myeloid and chronic lymphocytic leukemia determined by high-pressure liquid chromatography and mass spectrometry. 1469 58

Acetylation of the epsilon-amino group of lysine residues, or N(epsilon)-lysine acetylation, is an important post-translational modification known to occur in histones, transcription factors and other proteins. Since 1995, dozens of proteins have been discovered to possess intrinsic lysine acetyltransferase activity. Although most of these enzymes were first identified as histone acetyltransferases and then tested for activities towards other proteins, acetyltransferases only modifying non-histone proteins have also been identified. Lysine acetyltransferases form different groups, three of which are Gcn5/PCAF, p300/CBP and MYST proteins. While members of the former two groups mainly function as transcriptional co-activators, emerging evidence suggests that MYST proteins, such as Esa1, Sas2, MOF, TIP60, MOZ and MORF, have diverse roles in various nuclear processes. Aberrant lysine acetylation has been implicated in oncogenesis. The genes for p300, CBP, MOZ and MORF are rearranged in recurrent leukemia-associated chromosomal abnormalities. Consistent with their roles in leukemogenesis, these acetyltransferases interact with Runx1 (or AML1), one of the most frequent targets of chromosomal translocations in leukemia. Therefore, the diverse superfamily of lysine acetyltransferases executes an acetylation program that is important for different cellular processes and perturbation of such a program may cause the development of cancer and other diseases.
 ...
PMID:The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. 1496 Jul 13

Acute graft-versus-host disease (GVHD) and leukemic relapse are the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies have demonstrated that the dysregulation of proinflammatory cytokines and the loss of gastrointestinal tract integrity contribute to GVHD, whereas the donor cytotoxic responses are critical for graft-versus-leukemia (GVL) preservation. Suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials as an antitumor agent; it inhibits the activity of histone deacetylases and at low doses exhibits antiinflammatory effects by reducing the production of proinflammatory cytokines. Using two well characterized mouse models of BMT, we have studied the effects of SAHA on GVHD severity and GVL activity. Administration of SAHA from day +3 to day +7 after BMT reduced serum levels of the proinflammatory cytokines and decreased intestinal histopathology, clinical severity, and mortality from acute GVHD compared with vehicle-treated animals. However, SAHA had no effect on donor T cell proliferative and cytotoxic responses to host antigens in vivo or in vitro. When mice received lethal doses of tumor cells at the time of BMT, administration of SAHA did not impair GVL activity and resulted in significantly improved leukemia-free survival by using two different tumor and donor/recipient combinations. These findings reveal a critical role for histone deacetylase inhibition in the proinflammatory events contributing to GVHD and suggest that this class of pharmacologic agents may provide a strategy to reduce GVHD while preserving cytotoxic T cell responses to host antigens and maintaining beneficial GVL effects.
 ...
PMID:Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. 1500 2

Inappropriate transcriptional repression involving histone deacetylases (HDACs) is a prominent cause for the development of leukemia. We now identify faulty expression of a specific mediator of transcriptional repression in a solid tumor. Loss of the adenomatosis polyposis coli (APC) tumor suppressor induces HDAC2 expression depending on the Wnt pathway and c-Myc. Increased HDAC2 expression is found in the majority of human colon cancer explants, as well as in intestinal mucosa and polyps of APC-deficient mice. HDAC2 is required for, and sufficient on its own to prevent, apoptosis of colonic cancer cells. Interference with HDAC2 by valproic acid largely diminishes adenoma formation in APC(min) mice. These findings point toward HDAC2 as a particularly relevant potential target in cancer therapy.
 ...
PMID:Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. 1514 53

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.
 ...
PMID:Role of RUNX family members in transcriptional repression and gene silencing. 1515 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>