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Comparative Epigenetics Analyses of Acute and Chronic Leukemia  [PDF]
Zhang Yan, Dianjing Guo
Journal of Biosciences and Medicines (JBM) , 2015, DOI: 10.4236/jbm.2015.37002
Abstract: Comparative analysis of epigenetic alterations between acute and chronic leukemia, with an emphasis on histone modifications, was conducted. We focused on the promoter regions of the whole genomes as well as oncogenes. Our results revealed that obvious differential histone modifications pattern existed between the two subtypes. H3K27ac had a high tag density in the promoter region in both Dnd41 cell lines and K562 cell lines. H3K27ac and H3K4me1 had high correlation between the two cell lines of oncogenes. Similar results were also achieved in the promoter region of high expression genes in the Jurkat and K562 cell lines based on RNA-seq data. This suggested that H2K27ac and H3K4me1 were active regulators in leukemia cell lines.
Epigenetic Modifications in Pediatric Acute Lymphoblastic Leukemia  [PDF]
Michael J. Burke,Teena Bhatla
Frontiers in Pediatrics , 2014, DOI: 10.3389/fped.2014.00042
Abstract: Aberrant epigenetic modifications are well-recognized drivers for oncogenesis. Pediatric acute lymphoblastic leukemia (ALL) is no exception and serves as a model toward the significant impact these heritable alterations can have in leukemogenesis. In this brief review, we will focus on the main aspects of epigenetics, which control leukemogenesis in pediatric ALL, mainly DNA methylation, histone modification, and microRNA alterations. As we continue to gain better understanding of the driving mechanisms for pediatric ALL at both diagnosis and relapse, therapeutic interventions directed toward these pathways and mechanisms can be harnessed and introduced into clinical trials for pediatric ALL.
Epigenetic Silencing of the Circadian Clock Gene CRY1 is Associated with an Indolent Clinical Course in Chronic Lymphocytic Leukemia  [PDF]
Maher Hanoun, Lewin Eisele, Masako Suzuki, John M. Greally, Andreas Hüttmann, Semra Aydin, René Scholtysik, Ludger Klein-Hitpass, Ulrich Dührsen, Jan Dürig
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034347
Abstract: Disruption of circadian rhythm is believed to play a critical role in cancer development. Cryptochrome 1 (CRY1) is a core component of the mammalian circadian clock and we have previously shown its deregulated expression in a subgroup of patients with chronic lymphocytic leukemia (CLL). Using real-time RT-PCR in a cohort of 76 CLL patients and 35 normal blood donors we now demonstrate that differential CRY1 mRNA expression in high-risk (HR) CD38+/immunoglobulin variable heavy chain gene (IgVH) unmutated patients as compared to low-risk (LR) CD38?/IgVH mutated patients can be attributed to down-modulation of CRY1 in LR CLL cases. Analysis of the DNA methylation profile of the CRY1 promoter in a subgroup of 57 patients revealed that CRY1 expression in LR CLL cells is silenced by aberrant promoter CpG island hypermethylation. The methylation pattern of the CRY1 promoter proved to have high prognostic impact in CLL where aberrant promoter methylation predicted a favourable outcome. CRY1 mRNA transcript levels did not change over time in the majority of patients where sequential samples were available for analysis. We also compared the CRY1 expression in CLL with other lymphoid malignancies and observed epigenetic silencing of CRY1 in a patient with B cell acute lymphoblastic leukemia (B-ALL).
Laboratory diagnosis of chronic myelomonocytic leukemia and progression to acute leukemia in association with chronic lymphocytic leukemia: morphological features and immunophenotypic profile
Santos, Iris Mattos;Franzon, Carine Muniz Ribeiro;Koga, Adolfo Haruo;
Revista Brasileira de Hematologia e Hemoterapia , 2012, DOI: 10.5581/1516-8484.20120058
Abstract: chronic myelomonocytic leukemia is a clonal stem cell disorder that is characterized mainly by absolute peripheral monocytosis. this disease can present myeloproliferative and myelodysplastic characteristics. according to the classification established by the world health organization, chronic myelomonocytic leukemia is inserted in a group of myeloproliferative/myelodysplastic disorders; its diagnosis requires the presence of persistent monocytosis and dysplasia involving one or more myeloid cell lineages. furthermore, there should be an absence of the philadelphia chromosome and the bcr/abl fusion gene and less than 20% blasts in the blood or bone marrow. phenotypically, the cells in chronic myelomonocytic leukemia can present myelomonocytic antigens, such as cd33 and cd13, overexpressions of cd56 and cd2 and variable expressions of hla-dr, cd36, cd14, cd15, cd68 and cd64. the increase in the cd34 expression may be associated with a transformation into acute leukemia. cytogenetic alterations are frequent in chronic myelomonocytic leukemia, and molecular mutations such as nras have been identified. the present article reports on a case of chronic myelomonocytic leukemia, diagnosed by morphologic and phenotypical findings that, despite having been suggestive of acute monocytic leukemia, were differentiated through a detailed analysis of cell morphology. furthermore, typical cells of chronic lymphocytic leukemia were found, making this a rare finding.
Chronic meningitis by histoplasmosis: report of a child with acute myeloid leukemia
Pereira, G.H.;Pádua, S.S.;Park, M.V.F.;Muller, R.P.;Passos, R.M.A.;Menezes, Y.;
Brazilian Journal of Infectious Diseases , 2008, DOI: 10.1590/S1413-86702008000600026
Abstract: meningitis is a common evolution in progressive disseminated histoplasmosis in children, and is asymptomatic in many cases. in leukemia, the impaired of the t cells function can predispose to the disseminated form. the attributed mortality rate in this case is 20%-40% and the relapse rate is as high as 50%; therefore, prolonged treatment may be emphasized. we have described a child with acute myeloid leukemia (aml), that developed skin lesions and asymptomatic chronic meningitis, with a good evolution after prolonged treatment with amphotericin b deoxycholate followed by fluconazole.
Oxidative Stress and Antioxidant Status in Acute and Chronic Myeloid Leukemia Patients  [PDF]
Ullagaddi Rajeshwari, Iyer Shobha, Rao Raghunatha, Bondada Andallu
Open Journal of Blood Diseases (OJBD) , 2013, DOI: 10.4236/ojbd.2013.33A004
Abstract: Oxidative stress, a pervasive condition of increased number of reactive oxygen species, is now recognized to be prominent feature of various diseases and their progression. The relationship between antioxidants and levels of well-known markers of oxidative stress, measured as lipid peroxides and oxidized proteins reflect health indices. The aim of this study is to evaluate the extent of oxidative stress and antioxidant status in acute and chronic myeloid leukemia patients. The present study included 60 patients selected using standard questionnaire based on age, family history, Body Mass Index (BMI), dietary intake, with no other complications and 30 age and sex-matched healthy subjects. The median age of myeloid leukemia patients was 43 years and that of controls was 42 years. Out of 60 myeloid leukemia patients, 30 were in acute and 30 were in chronic state. Oxidative stress and antioxidant status were evaluated in the patients and in the controls by assessing standard oxidative stress markers viz. plasma and erythrocyte lipid peroxide levels in terms of malondialdehyde and oxidized proteins as protein carbonyls whereas antioxidant status was assessed in terms of serum non enzymatic antioxidant levels. There was a significant increase (p < 0.01) in plasma and erythrocyte lipid peroxidation and protein oxidation in acute and chronic myeloid leukemia patients as compared to healthy subjects. Antioxidant status as indicated by the levels of non-enzymatic antioxidants viz. erythrocyte reduced glutathione (GSH), serum β carotene, vitamin A & C and ceruloplasmin was found to be significantly decreased (p < 0.01) in both the leukemia patients as compared to healthy participants. However, chronic myeloid leukemia patients had significantly (p < 0.05) higher oxidative stress and lower antioxidant status as compared to acute myeloid leukemia patients.
Epigenetic Inactivation of Notch-Hes Pathway in Human B-Cell Acute Lymphoblastic Leukemia  [PDF]
Shao-Qing Kuang, Zhihong Fang, Patrick A. Zweidler-McKay, Hui Yang, Yue Wei, Emilio A. Gonzalez-Cervantes, Yanis Boumber, Guillermo Garcia-Manero
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061807
Abstract: The Notch pathway can have both oncogenic and tumor suppressor roles, depending on cell context. For example, Notch signaling promotes T cell differentiation and is leukemogenic in T cells, whereas it inhibits early B cell differentiation and acts as a tumor suppressor in B cell leukemia where it induces growth arrest and apoptosis. The regulatory mechanisms that contribute to these opposing roles are not understood. Aberrant promoter DNA methylation and histone modifications are associated with silencing of tumor suppressor genes and have been implicated in leukemogenesis. Using methylated CpG island amplification (MCA)/DNA promoter microarray, we identified Notch3 and Hes5 as hypermethylated in human B cell acute lymphoblastic leukemia (ALL). We investigated the methylation status of other Notch pathway genes by bisulfite pyrosequencing. Notch3, JAG1, Hes2, Hes4 and Hes5 were frequently hypermethylated in B leukemia cell lines and primary B-ALL, in contrast to T-ALL cell lines and patient samples. Aberrant methylation of Notch3 and Hes5 in B-ALL was associated with gene silencing and was accompanied by decrease of H3K4 trimethylation and H3K9 acetylation and gain of H3K9 trimethylation and H3K27 trimethylation. 5-aza-2′-deoxycytidine treatment restored Hes5 expression and decreased promoter hypermethylation in most leukemia cell lines and primary B-ALL samples. Restoration of Hes5 expression by lentiviral transduction resulted in growth arrest and apoptosis in Hes5 negative B-ALL cells but not in Hes5 expressing T-ALL cells. These data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL.
Detection of mutator phenotype in Brazilian patients with acute and chronic myeloid leukemia
Ayres, Flávio Monteiro;Momotuk, Euza Guimar?es;Bastos, Celso da Cunha;Cruz, Aparecido Divino da;
Genetics and Molecular Biology , 2004, DOI: 10.1590/S1415-47572004000400003
Abstract: the multisteps of tumorigenesis involve the classic chromosomal instability and the mutator phenotype pathways featured by a predisposition to acquire mutations in tumor suppressor genes and oncogenes. expansion and contraction of microsatellite sequences due to a deficient mismatch repair system are a marker of the mutator phenotype. controversial results regarding the extent of microsatellite instability (msi) have been reported in the development and progression of myeloid malignancies. here, we investigated msi and loss of heterozygosity (loh) frequencies at the microsatellite loci bat-26, d7s486, d8s135, ank1, ifna, tp53 and bcr of 19 brazilian patients with acute (aml) and chronic myeloid leukemia (cml). one aml patient and one cml patient were categorized as having a high degree of microsatellite instability (msi-h), corresponding to 10.5% (2/19) of all patients. loh at loci bat-26 and tp53 was present in 30% of the patients with aml alone. despite the small sample size, our results suggest that the mutator phenotype, as verified by msi frequency, could play a role in the leukemogenesis of a small subset of patients with myeloid leukemia.
Frequent and Simultaneous Epigenetic Inactivation of TP53 Pathway Genes in Acute Lymphoblastic Leukemia  [PDF]
Amaia Vilas–Zornoza,Xabier Agirre,Vanesa Martín-Palanco,José Ignacio Martín-Subero,Edurne San José-Eneriz,Leire Garate,Sara álvarez,Estíbaliz Miranda,Paula Rodríguez-Otero,José Rifón,Antonio Torres,María José Calasanz,Juan Cruz Cigudosa,José Román-Gómez,Felipe Prósper
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017012
Abstract: Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2′-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p = 0.006) and overall survival (OS) (p = 0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.
CD7 in acute myeloid leukemia: correlation with loss of wild-type CEBPA, consequence of epigenetic regulation
Sonja R?hrs, Michaela Scherr, Julia Romani, Margarete Zaborski, Hans G Drexler, Hilmar Quentmeier
Journal of Hematology & Oncology , 2010, DOI: 10.1186/1756-8722-3-15
Abstract: As already described for primary AML cells, the majority of AML cell lines tested were either C/EBPα+/CD7- or C/EBPα-/CD7+. However, the existence of isolated CD7+ cell lines expressing wild-type C/EBPα challenges the notion that C/EBPα acts as a unique repressor of CD7. Furthermore, ectopic expression of CEBPA did not reduce CD7 in CD7+ cells and knock-down of C/EBPα failed to induce CD7 in CD7- cells. In contrast, the DNA demethylating agent Aza-2'deoxycytidine triggered CD7 expression in CD7- AML and in T-cell lines suggesting epigenetic regulation of CD7. Bisulfite sequencing data confirmed that CpGs in the CD7 exon1 region are methylated in CD7- cell lines, and unmethylated in CD7+ cell lines.We confirmed an inverse correlation between the expression of wild-type CEBPA and of CD7 in AML cells. Our results contradict the hypothesis that C/EBPα acts as repressor for CD7, and instead show that epigenetic mechanisms are responsible for CD7 regulation, in AML cells as well as in T-cells, the typical CD7 expressing cell type.CCAAT/enhancer binding factor alpha (CEBPA), located on chromosome 19q13.1 encodes a transcription factor that is of importance for granulocytic differentiation [1]. C/EBPα is upregulated during myelomonocytic development and positively affects expression of granulocyte differentiation related genes such as the G-CSF receptor (GCSFR), myeloperoxidase and neutrophil elastase (ELA2) [2-4]. CEBPA mutations are found in 5 - 14% of acute myeloid leukemia (AML) cases [5]. C/EBPα mutant proteins block the effect of wild-type C/EBPα on target genes in a dominant-negative manner [6]. This might be the reason why patients with CEBPA mutations and those with a silenced CEBPA promoter are found in the same AML subclass according to gene expression profiling [7]. Also expression of the T-cell marker CD7 has been associated with CEBPA mutations and with CEBPA hypermethylation [7,8].CD7 is expressed in 30% of AML cases and CD7 positivity is linked with poor pro
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