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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymus, an important component of hematopoietic tissue, is a well-documented "target" of radiation carcinogenesis. Both acute and fractionated irradiation result in a high risk of leukemia and thymic lymphoma. However, the exact mechanisms underlying radiation-induced predisposition to leukemia and lymphoma are still unknown, and the contributions of genetic and epigenetic mechanisms in particular have yet to be defined. Global DNA hypomethylation is a well-known characteristic of cancer cells. Recent studies have also shown that tumor cells undergo prominent changes in histone methylation, particularly a substantial loss of trimethylation of histone H4-Lys20 and demethylation of genomic DNA. These losses are considered a universal marker of malignant transformation. In the present study, we investigated the effect of low-dose radiation exposure on the accumulation of DNA lesions and alterations of DNA methylation and histone H4-Lys20 trimethylation in the thymus tissue using an in vivo murine model. For the first time, we show that fractionated whole-body application of 0.5 Gy X-ray leads to decrease in histone H4-Lys20 trimethylation in the thymus. The loss of histone H4-Lys20 trimethylation was accompanied by a significant decrease in global DNA methylation as well as the accumulation of DNA damage as monitored by persistence of histone gammaH2AX foci in the thymus tissue of mice exposed to fractionated irradiation. Altered DNA methylation was associated with reduced expression of maintenance (DNMT1) and, to a lesser extent, de novo DNA methyltransferase DNMT3a in exposed animals. Expression of another de novo DNA methyltransferase DNMT3b was decreased only in males. Irradiation also resulted in approximately 20% reduction in the levels of methyl-binding proteins MeCP2 and MBD2. Our results show the involvement of epigenetic alterations in radiation-induced responses in vivo. These changes may play a role in genome destabilization that ultimately leads to cancer.
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PMID:Fractionated low-dose radiation exposure leads to accumulation of DNA damage and profound alterations in DNA and histone methylation in the murine thymus. 1625 89

Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.
Leukemia 2006 Feb
PMID:Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. 1635 41

Nuclear events such as chromatin condensation, DNA cleavage at internucleosomal sites, and histone release from chromatin are recognized as hallmarks of apoptosis. However, there is no complete understanding of the molecular events underlying these changes. It is likely that epigenetic changes such as DNA methylation and histone modifications that are involved in chromatin dynamics and structure are also involved in the nuclear events described. In this report we have shown that apoptosis is associated with global DNA hypomethylation and histone deacetylation events in leukemia cells. Most importantly, we have observed a particular epigenetic signature for early apoptosis defined by a release of hypoacetylated and trimethylated histone H4 and internucleosomal fragmented DNA that is hypermethylated and originates from perinuclear heterochromatin. These findings provide one of the first links between apoptotic nuclear events and epigenetic markers.
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PMID:Release of hypoacetylated and trimethylated histone H4 is an epigenetic marker of early apoptosis. 1653 10

Histone deacetylase inhibitors have a potent role in the strategy for the treatment of leukemias. BML-210 (N-(2-Aminophenyl)-N' phenyloctanol diamine) is the novel histone deacetylase inhibitor, and its mechanism of action has not been characterized. In this study, we examined the in vitro effects of BML-210 on the human leukemia cell lines (NB4, HL-60, THP-1, and K562). We found that BML-210 inhibits the growth of all cell lines and promotes apoptosis in a dose- and time-dependent manner. BML-210 alone induces HL-60 and K562 cell differentiation (up to 30%) to granulocytes and erythrocytes, respectively, and in combination with differentiation agents - all-trans retinoic acid and hemin, markedly potentates it. Those treatments cause G1 arrest and histone H4 acetylation, affects transcription factor NF-kappaB and Sp1 binding activity to their consensus sequences, the p21 or the FasL promoters, and influences expression of Sp1, NF-kappaB, p21 and FasL. These findings suggest that BML-210 could be a promising antileukemic agent to induce apoptosis and to modulate differentiation through the modulation of histone acetylation and gene expression.
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PMID:The novel histone deacetylase inhibitor BML-210 exerts growth inhibitory, proapoptotic and differentiation stimulating effects on the human leukemia cell lines. 1697 4

In a previous study, we demonstrated immunoreactivity of a subset of neuronal intranuclear rodlets (INRs) in the human substantia nigra for promyelocytic leukaemia (PML) protein, the signature protein of PML bodies. In the present study, we extend these observations and describe the ultrastructural features, immunohistochemical staining characteristics, and topographical pattern of distribution of PML-immunoreactive intranuclear rodlets (PML-INRs). Consistent with a purported role for PML bodies in nuclear proteolysis and/or transcriptional regulation, PML-INRs are immunoreactive for components of the ubiquitin-proteasome system, the transcriptional regulator CREB-binding protein, acetylated histone H4, and the eukaryotic translation initiation factor eIF4E. Immunoelectron microscopy reveals that they all possess a filamentous core and, in some, this is surrounded by a granular shell. We further demonstrate that a proportion of INRs in extranigral sites also show partial immunoreactivity for PML. These observations indicate an intimate association between two neuronal nuclear bodies, PML bodies and INRs. Because both of these structures have been implicated in neurodegenerative disease, PML-INRs may provide a tool with which to study changes in nuclear substructure in disease.
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PMID:Promyelocytic leukaemia-immunoreactive neuronal intranuclear rodlets in the human brain. 1723 8

FK228 (depsipeptide) is a novel histone deacetylase inhibitor (HDACI) that has shown therapeutical efficacy in clinical trials for malignant lymphoma. In this article, we examined in vitro effects of FK228 on human leukemia cell lines, NB4 and HL-60. FK228 alone (0.2-1 ng/mL) inhibited leukemia cell growth in a dose-dependent manner and induced death by apoptosis. FK228 had selective differentiating effects on two cell lines when used for 6 h before induction of granulocytic differentiation by retinoic acid (RA) or in combination with RA. These effects were accompanied by a time- and dose-dependent histone H4 hyper-acetylation or histone H3 dephosphorylation and alterations in DNA binding of NF-kappaB in association with cell death and differentiation. Pifithrin-alpha (PFT), an inhibitor of p53 transcriptional activity, protected only NB4 cells with functional p53 from FK228-induced apoptosis and did not interfere with antiproliferative activity in p53-negative HL-60 cells. In NB4 cells, PFT inhibited p53 binding to the p21 (Waf1/Cip1) promotor and induced DNA binding of NF-kappaB leading to enhanced cell survival. Thus, beneficial effects of FK228 on human promyelocytic leukemia may be exerted through the induction of differentiation or apoptosis via histone modification and selective involvement of transcription factors, such as NF-kappaB and p53.
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PMID:The histone deacetylase inhibitor FK228 distinctly sensitizes the human leukemia cells to retinoic acid-induced differentiation. 1734 29

FR235222, a novel histone deacetylase inhibitor (HDACi), at 50nM caused accumulation of acetylated histone H4, inhibition of cell proliferation and G1 cycle arrest accompanied by increase of p21 and down-regulation of cyclin E in human promyelocytic leukaemia U937 cells. The compound was also able to increase the protein and mRNA levels of annexin A1 (ANXA1) without effects on apoptosis. Similar effects were observed in human chronic myelogenous leukaemia K562 cells and human T cell leukaemia Jurkat cells. Cycle arrest and ANXA1 expression, without significant effects on apoptosis, were also induced by different HDACi like suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). FR235222 at 0.5 microM stimulated apoptosis of all leukaemia cell lines associated to an increased expression of the full-length (37kDa) protein and the appearance of a 33kDa N-terminal cleavage product in both cytosol and membrane. These results suggest that ANXA1 expression may mediate cycle arrest induced by low doses FR235222, whereas apoptosis induced by high doses FR235222 is associated to ANXA1 processing.
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PMID:Effects of FR235222, a novel HDAC inhibitor, in proliferation and apoptosis of human leukaemia cell lines: role of annexin A1. 1829 77

Polycomb repressive complex 2 (PRC2), which mediates trimethylation of lysine 27 on histone H3 (K27me3), plays an important role in many types of stem cell differentiation. Here, we try to reveal how PRC2, PRC2-mediated repressive histone marker H3K27me3, and active histone marker histone H4 acetylation (acH4) regulate the CD11b transcription during alltrans retinoic acid (ATRA)-induced HL-60 leukemia cell differentiation. By using quantitative real-time polymerase chain reaction (qPCR) and western blot analysis, we found that the mRNA and protein expression levels of two members of PRC2 were decreased during ATRA-induced HL-60 differentiation, respectively. When treated with ATRA for 72 h, the EZH2 and SUZ12 mRNA levels were decreased to 35% and 38% of the control group, respectively. At the same time, the granulocytic mature surface marker CD11b expression was increased significantly at mRNA level detected by qPCR and protein level detected by flow cytometry. By using chromatin immunoprecipitation assay, we compared the local changes in SUZ12 binding and PRC2-mediated H3K27me3 at the promoter of CD11b during ATRA-induced HL-60 differentiation. Both the levels of SUZ12 binding and PRC2-mediated H3K27me3 at the promoter of CD11b were decreased for 4.1 and 3.8 folds, respectively. And we also found the increase in the acH4 level up to 4 folds after 72 h of ATRA treatment. These results suggested that the histone modification including PRC2-mediated repressive histone marker H3K27me3 and active histone marker acH4 may involve in CD11b transcription during HL-60 leukemia cells reprogramming to terminal differentiation.
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PMID:Regulation of CD11b transcription by decreasing PRC2 and increased acH4 level during ATRA-induced HL-60 differentiation. 1957 22

Propionylation has been identified recently as a new type of protein post-translational modification. Bacterial propionyl-CoA synthetase and human histone H4 are propionylated at specific lysine residues that have been known previously to be acetylated. However, other proteins subject to this modification remain to be identified, and the modifying enzymes involved need to be characterized. In this work, we report the discovery of histone H3 propionylation in mammalian cells. Propionylation at H3 lysine Lys(23) was detected in the leukemia cell line U937 by mass spectrometry and Western analysis using a specific antibody. In this cell line, the propionylated form of Lys(23) accounted for 7%, a level at least 6-fold higher than in other leukemia cell lines (HL-60 and THP-1) or non-leukemia cell lines (HeLa and IMR-90). The propionylation level in U937 cells decreased remarkably during monocytic differentiation, indicating that this modification is dynamically regulated. Moreover, in vitro assays demonstrated that histone acetyltransferase p300 can catalyze H3 Lys(23) propionylation, whereas histone deacetylase Sir2 can remove this modification in the presence of NAD(+). These results suggest that histone propionylation might be generated by the same set of enzymes as for histone acetylation and that selection of donor molecules (propionyl-CoA versus acetyl-CoA) may determine the difference of modifications. Because like acetyl-CoA, propionyl-CoA is an important intermediate in biosynthesis and energy production, histone H3 Lys(23) propionylation may provide a novel epigenetic regulatory mark for cell metabolism.
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PMID:Identification and characterization of propionylation at histone H3 lysine 23 in mammalian cells. 1980 1

The AML1-ETO fusion protein, which is present in 10-15% of cases of acute myeloid leukemia, is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1-ETO fusion gene enabled us to identify 1168 AML1-ETO target genes, 103 of which were co-occupied by histone deacetylase 1 (HDAC1) and had lost the hyperacetylation mark at histone H4, and 264 showed a K9 trimethylation at histone H3. Enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways was observed in the presence of these epigenetic modifications associated with an 'inactive' chromatin status. Furthermore, AML1-ETO target genes had a significant correlation between the chromatin marks studied and transcriptional silencing. Interestingly, AML1 binding sites were absent on a large number of selected AML1-ETO promoters and an Sp1 binding site was found in over 50% of them. Reversible silencing induced by the fusion protein in the presence of AML1 and/or Sp1 transcription factor binding site was confirmed. Therefore, this study provides a global analysis of AML1-ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA binding pattern of AML1-ETO, suggesting a role for Sp1-targeted therapy in this leukemia subtype.
Leukemia 2012 Jun
PMID:Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs. 2228 84


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