Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myeloid leukemia (AML) is still associated with a mortality of 60 to 80%. AML is characterized by a block in myeloid differentiation. The transcription factors PU.1 and C/EBPalpha are responsible for normal myeloid differentiation from stem cells to monocytes or granulocytes. In particular, PU.1 induces expression of the macrophage colony-stimulating factor (M-CSF) receptor and the development of monocytes, whereas C/EBPalpha increases the expression of the granulocyte colony-stimulating factor (G-CSF) receptor and leads to mature granulocytes. In AML, chromosomal aberrations result in oncoproteins such as AML1/ETO, PML/RARalpha, or activated Ras, which can deregulate genes important for normal myelopoiesis. Thus, AML1/ETO can bind to the transcription factor C/EBPalpha, inhibit C/EBPalpha-dependent transcription, and block granulocytic differentiation. However, AML1/ETO can also synergize with the transcription factor AML1 to enhance the activity of the M-CSF receptor promoter. On the other hand, the PML/RARalpha fusion protein causes transcriptional repression by recruiting the nuclear corepressor (N-CoR) histone deacetylase complex to the DNA, which results in decreased histone acetylation and a repressive chromatin organization. Here we describe methods to investigate whether and how signaling agonists induce myeloid differentiation and how oncoproteins might cause AML by modulating the activity of transcription factors that are pivotal for normal myeloid development.
 ...
PMID:Analysis of the modulation of transcriptional activity in myelopoiesis and leukemogenesis. 1008 Sep 8

The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1-ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor alpha in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.
 ...
PMID:The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein. 1068 54

New agents for the treatment of acute myelogenous leukemia are discussed that reflect different treatment mechanisms. These include histone acetylation, angiogenesis inhibition, protein kinase inhibitors, and a novel retinoid. Efficacy and safety in phase I and phase II trials reviewed, as well as the problems involved in crossing over from treatment of solid tumors to blood disorders.
 ...
PMID:New agents for acute myelogenous leukemia. 1072 Jan 47

Successful treatment of acute promyelocytic leukemia (APL) has identified several novel approaches to induce leukemic cell differentiation and selective apoptosis by overcoming the site-specific transcriptional repression by dominant fusion leukemogenic proteins characteristic of APL and other forms of acute myelogenous leukemia (AML). These therapeutic approaches include the use of site-specific ligands, receptors and cytokines, disruption of dominant fusion leukemogenic proteins, chromatin remodeling and combining the above with cytotoxic chemotherapy. With the exception of cytotoxic chemotherapy, the above therapeutic strategies do not significantly affect normal hematopoiesis and their combinations have been shown to be synergistic in inducing myeloid differentiation and apoptosis in several AML cell lines and in patients with APL. These approaches are, in general, non-cross resistant and should be well tolerated particularly in elderly patients with AML. Clinical studies which include biologic end points for differentiation induction, histone acetylation and selective apoptosis are presently in development to evaluate these strategies in the treatment of AML.
 ...
PMID:Differentiation therapy in acute myelogenous leukemia (non-APL). 1072 Jan 48

Chromatin remodeling at eukaryotic gene promoter sequences accompanies transcriptional activation. Both molecular events rely on specific protein-DNA interactions that occur within these promoter sequences. Binding of CBFalpha/AML/PEBP2alpha (core binding factor alpha/acute myelogenous leukemia/polyoma enhancer binding protein 2alpha) proteins is a key event in both tissue-specific and developmentally regulated osteocalcin (OC) promoter activity. To address linkage between chromatin organization and transcription factor binding, we reconstituted segments of the rat OC gene proximal promoter into mononucleosomes and studied binding of CBFalpha proteins. We analyzed binding of bacterially produced Cbfalpha2Alpha and Cbfalpha2B, two splice variants of the human CBFalpha2 gene, and determined the effect of heterodimerization with the Cbfbeta subunit on binding activity. Our results indicate that binding of the truncated Cbfalpha2A protein to naked DNA is independent of Cbfbeta whereas Cbfalpha2A binding to nucleosomal DNA was enhanced by Cbfbeta. In contrast, the Cbfalpha2B interaction with either naked or nucleosomal DNA was strongly dependent on heterodimerization with the Cbfbeta subunit. Additionally, our results demonstrate that both Cbfalpha2A alone and Cbfalpha2B complexed with Cbfbeta can interact with nucleosomal DNA only if there is a degree of flexibility in the positioning of the histone octamer on the DNA fragment and exposure of the CBFalpha site. This situation was achieved with a DNA segment of 182 bp from the rat OC promoter that preferentially positions mononucleosomes upstream of the CBFalpha binding site and leaves this element partially exposed. Taken together, these results suggest that nucleosomal translational positioning is a major determinant of the binding of CBFalpha factors to nucleosomal DNA.
 ...
PMID:Interaction of CBF alpha/AML/PEBP2 alpha transcription factors with nucleosomes containing promoter sequences requires flexibility in the translational positioning of the histone octamer and exposure of the CBF alpha site. 1106 94

Histone acetyltransferase p300 functions as a transcriptional co-activator which interacts with a number of transcription factors. Monocytic leukemia zinc finger protein (MOZ) has histone acetyltransferase activity. We report the fusion of the MOZ gene to the p300 gene in acute myeloid leukemia with translocation t(8;22)(p11;q13). FISH and Southern blot analyses showed the rearrangement of the MOZ and p300 genes. We determined the genomic structure of the p300 and the MOZ genes and the breakpoints of the translocation. Analysis of fusion transcripts indicated that the zinc finger and acetyltransferase domains of MOZ are fused to a largely intact p300. These results suggest that MOZ-p300, which has two acetyltransferase domains, could be involved in leukemogenesis through aberrant regulation of histone acetylation.
 ...
PMID:Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation. 1124 5

Transcriptional regulation at the level of chromatin plays crucial roles during eukaryotic development and differentiation. A plethora of studies revealed that the acetylation status of histones is controlled by multi-protein complexes containing (de)acetylase activities. In the current model, histone deacetylases and acetyltransferases are recruited to chromatin by DNA-bound repressors and activators, respectively. Shifting the balance between deacetylation, i.e. repressive chromatin and acetylation, i.e. active chromatin can lead to aberrant gene transcription and cancer. In human acute promyelocytic leukemia (APL) and avian erythroleukemia (AEL), chromosomal translocations and/or mutations in nuclear hormone receptors, RARalpha [NR1B1] and TRalpha [NR1A1], yielded oncoproteins that deregulate transcription and alter chromatin structure. The oncogenic receptors are locked in their 'off' mode thereby constitutively repressing transcription of genes that are critical for differentiation of hematopoietic cells. AEL involves an oncogenic version of the chicken TRalpha, v-ErbA. Apart from repression by v-ErbA via recruitment of corepressor complexes, other repressors and corepressors appear to be involved in repression of v-ErbA target genes, such as carbonic anhydrase II (CAII). Reactivation of repressed genes in APL and AEL by chromatin modifying agents such as inhibitors of histone deacetylase or of methylation provides new therapeutic strategies in the treatment of acute myeloid leukemia.
 ...
PMID:Avian erythroleukemia: a model for corepressor function in cancer. 1142 Jul 26

t(8;21) and t(16;21) create two fusion proteins, AML-1-ETO and AML-1-MTG16, respectively, which fuse the AML-1 DNA binding domain to putative transcriptional corepressors, ETO and MTG16. Here, we show that distinct domains of ETO contact the mSin3A and N-CoR corepressors and define two binding sites within ETO for each of these corepressors. In addition, of eight histone deacetylases (HDACs) tested, only the class I HDACs HDAC-1, HDAC-2, and HDAC-3 bind ETO. However, these HDACs bind ETO through different domains. We also show that the murine homologue of MTG16, ETO-2, is also a transcriptional corepressor that works through a similar but distinct mechanism. Like ETO, ETO-2 interacts with N-CoR, but ETO-2 fails to bind mSin3A. Furthermore, ETO-2 binds HDAC-1, HDAC-2, and HDAC-3 but also interacts with HDAC-6 and HDAC-8. In addition, we show that expression of AML-1-ETO causes disruption of the cell cycle in the G(1) phase. Disruption of the cell cycle required the ability of AML-1-ETO to repress transcription because a mutant of AML-1-ETO, Delta469, which removes the majority of the corepressor binding sites, had no phenotype. Moreover, treatment of AML-1-ETO-expressing cells with trichostatin A, an HDAC inhibitor, restored cell cycle control. Thus, AML-1-ETO makes distinct contacts with multiple HDACs and an HDAC inhibitor biologically inactivates this fusion protein.
 ...
PMID:ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain. 1153 36

AML-1 is one of the most frequently translocated genes in human leukemia. AML-1 binds DNA and activates or represses transcription, while the chromosomal translocation fusion proteins in acute myeloid leukemia subvert these functions. The t(8;21) is the second most frequent translocation in acute myeloid leukemia and creates a fusion between the DNA binding domain of AML-1 and the ETO (also known as MTG8) corepressor. The t(12;21) is found in up to 25% of pediatric B cell acute lymphoblastic leukemias and fuses the ETS family transcription factor TEL to the amino terminus of AML-1. In addition, the inv(16), the most frequent translocation in acute myeloid leukemia, fuses the AML-1 cofactor CBFbeta to the smooth muscle myosin heavy chain MYH11. Both the t(8;21) and t(12;21) create transcriptional repressors that impair AML-1 target gene expression. We demonstrated that the fusion proteins encoded by these translocations contact the nuclear hormone corepressors (N-CoR/SMRT), mSin3A, and histone deacetylases. We have also found that both TEL and AML-1 interact with mSin3A. TEL also binds N-CoR and histone deacetylase-3, indicating that wild-type TEL is a transcriptional repressor. The t(12;21) fuses the mSin3A interaction domain of TEL to AML-1 to transform AML-1 from a regulated to an unregulated transcriptional repressor. The recognition that AML-1 interacts with mSin3A to repress transcription suggested that the inv(16) fusion protein might also repress the transcription of AML-1-target genes. In fact, the inv(16) encodes a protein that cooperates with AML-1 to repress transcription. The inv(16) fusion protein was found in a ternary complex with AML-1 and mSin3A, suggesting that the inv(16) also acts by recruiting transcriptional corepressors and histone deacetylases.
 ...
PMID:Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins. 1158 63

The therapeutic dilemma that confronts the management of patients with myelodysplastic syndromes (MDS) is illustrated by the absence of a Food and Drug Administration-approved agent with an indication for this disease. Clinical heterogeneity and inadequate understanding of the disease pathobiology have limited progress in the development of novel therapeutics. Preclinical investigations indicate that reciprocal interaction between the malignant clone and the microenvironment serve to create a hostile milieu that reinforces ineffective blood cell production. Ineffective hematopoiesis, the hallmark of MDS, arises from impaired progenitor responsiveness to normal trophic signals and excess local generation of inhibitory cytokines, which promote accelerated apoptotic loss of progenitors and their progeny. Evidence to support this model derives from cytokine neutralization studies and the direct relationship between plasma tumor necrosis factor-alpha concentration and DNA oxidation and glutathione depletion in malignant CD34+ progenitors. Recent investigations indicate that angiogenic molecules generated by malignant myelomonocytic precursors represent integral diffusable signals that reinforce leukemia progenitor self-renewal while promoting the generation of proapoptotic cytokines and medullary angiogenic response. The potential for leukemia evolution is compounded by epigenetic events including methylation silencing of the p15 proto-oncogene or activating ras point mutations. Delineation of such biologic features that are central to the pathobiology of MDS provides a reliable framework for the development of novel therapeutics. Antiangiogenic agents in clinical testing include vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, thalidomide and related analogues, and the recombinant VEGF neutralizing antibody, bevacizumab. Agents whose actions may restore differentiation programs, such as the DNA methyltransferase inhibitors or histone deacetylase inhibitors, offer the prospect to promote effective hematopoiesis while impacting the potential for leukemia evolution. RAS farnesyl transferase inhibitors have shown encouraging preliminary results in acute myeloid leukemia and are currently under investigation in advanced MDS and chronic myelomonocytic leukemia. Arsenic trioxide (ATO) interacts with a spectrum of biologic targets that may be uniquely suited to MDS. ATO is a potent inducer of apoptosis in thiol-depleted malignant progenitors and neovascular endothelium, while promoting differentiation through histone acetylation and inactivation of transcriptional corepressors. The identification of relevant biologic targets in MDS has raised expectations for the development of disease-specific therapies for MDS in the years that follow.
 ...
PMID:New approaches to the treatment of myelodysplasia. 1196 Dec 8


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