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      Molecular characteristics and chromatin texture features in acute promyelocytic leukemia

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          Abstract

          Background

          Acute promyelocytic leukemia is a cytogenetically well defined entity. Nevertheless, some features observed at diagnosis are related to a worse outcome of the patients.

          Methods

          In a prospective study, we analyzed peripheral (PB) leukocyte count, immunophenotype, methylation status of CDKN2B, CDKN2A and TP73; FLT3 and NPM1 mutations besides nuclear chromatin texture characteristics of the leukemic cells. We also examined the relation of these features with patient’s outcome.

          Results

          Among 19 cases, 4 had a microgranular morphology, 7 presented PB leukocytes >10x10 9/l, 2 had FLT3-ITD and 3 had FLT3-TKD (all three presenting a methylated CDKN2B). NPM1 mutation was not observed. PB leukocyte count showed an inverse relation with standard deviation of gray levels, contrast, cluster prominence, and chromatin fractal dimension (FD). Cases with FLT3-ITD presented a microgranular morphology, PB leukocytosis and expression of HLA-DR, CD34 and CD11b. Concerning nuclear chromatin texture variables, these cases had a lower entropy, contrast, cluster prominence and FD, but higher local homogeneity, and R 245, in keeping with more homogeneously distributed chromatin. In the univariate Cox analysis, a higher leukocyte count, FLT3-ITD mutation, microgranular morphology, methylation of CDKN2B, besides a higher local homogeneity of nuclear chromatin, a lower chromatin entropy and FD were associated to a worse outcome. All these features lost significance when the cases were stratified for FLT3-ITD mutation. Methylation status of CDNK2A and TP73 showed no relation to patient’s survival.

          Conclusion

          in APL, patients with FLT3-ITD mutation show different clinical characteristics and have blasts with a more homogeneous chromatin texture. Texture analysis demonstrated that FLTD-ITD was accompanied not only by different cytoplasmic features, but also by a change in chromatin structure in routine cytologic preparations. Yet we were not able to detect chromatin changes by nuclear texture analysis of patients with the FTLD-TKD or methylation of specific genes.

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          Most cited references43

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          DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.

          We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates). Copyright (c) 2010 Elsevier Inc. All rights reserved.
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            Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet.

            The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion-based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.
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              The fundamental role of epigenetics in hematopoietic malignancies.

              The term epigenetics defines a heritable alteration in gene expression without an accompanying change in primary DNA sequence. Two major mechanisms that foster epigenetic changes are DNA methylation at cytosine bases within a CpG dinucleotide and post-translational histone modifications. Disruption of the balanced epigenetic network may have significant impact on chromatin structure and transcriptional activity. DNA methylation patterns are profoundly deranged in human cancer and comprise genome-wide losses as well as regional gains in DNA methylation. Hypermethylation of CpG islands within gene promoter regions in collaboration with deacetylation and other modifications of key histone amino acids is associated with transcriptional inactivation and represents, in addition to genetic aberrations, an important mechanism of gene silencing in the pathogenesis of human cancer. These epigenetic events act as alternatives to mutations and deletions to disrupt tumor suppressor gene function. A large number of genes involving fundamental cellular pathways may be affected by aberrant CpG island methylation in association with transcriptional silencing in virtually all tumor types. Altered DNA methylation patterns may serve as biomarkers for cancer detection, assessment of prognosis, and prediction of response to therapy. Furthermore, clinical trials using epigenetically targeted therapies have yielded promising results in hematopoietic malignancies. The ongoing exploration of basic events involved in altered gene transcription patterns and continued clinical investigative studies are helping to develop novel strategies for the diagnosis, prevention, and treatment of human cancer.
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                Author and article information

                Journal
                Diagn Pathol
                Diagn Pathol
                Diagnostic Pathology
                BioMed Central
                1746-1596
                2012
                28 June 2012
                : 7
                : 75
                Affiliations
                [1 ]Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Rua Tessalia Vieira de Camargo 126, 13083-887, Campinas, Brazil
                [2 ]Hematology/Hemotherapy Center, State University of Campinas, Rua Carlos Chagas 480, 13083-878, Campinas, SP, Brazil
                [3 ]Department of Pathology, Faculty of Medical Sciences, State University of Campinas, Rua Tessalia Vieira de Camargo 126, 13083-887, Campinas, Brazil
                Article
                1746-1596-7-75
                10.1186/1746-1596-7-75
                3478223
                22742960
                814cd832-0e30-4ca0-91df-6b21fe4f2abb
                Copyright ©2012 Mello et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 4 April 2012
                : 21 May 2012
                Categories
                Research

                Pathology
                chromatin texture,promyelocytic leukemia,prognosis,flt3-itd
                Pathology
                chromatin texture, promyelocytic leukemia, prognosis, flt3-itd

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