scholarly journals Combination of myeloproliferative neoplasm driver gene activation with mutations of splice factor or epigenetic modifier genes increases risk of rapid blastic progression

2021 ◽  
Author(s):  
Stephan Bartels ◽  
Julia Vogtmann ◽  
Elisa Schipper ◽  
Guntram Büsche ◽  
Jerome Schlue ◽  
...  
Keyword(s):  
Gene Activation ◽  
Myeloproliferative Neoplasm ◽  
Splice Factor ◽  
Modifier Genes ◽  
Driver Gene ◽  
Epigenetic Modifier

scholarly journals Lineage-Specific Regulation of Epigenetic Modifier Genes in Human Liver and Brain

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e102035 ◽  
Author(s):  
Matthias K. Weng ◽  
Karthick Natarajan ◽  
Diana Scholz ◽  
Violeta N. Ivanova ◽  
Agapios Sachinidis ◽  
...  
Keyword(s):  
Human Liver ◽  
Modifier Genes ◽  
Epigenetic Modifier ◽  
Specific Regulation

scholarly journals Shared Genomic Alterations in Patients with Co-Existing Myeloproliferative Neoplasms and Angioimmunoblastic T-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2776-2776
Author(s):  
Johanne Marie Holst ◽  
Martin Bjerregaard Pedersen ◽  
Marcus C Hansen ◽  
Trine Lindhardt Plesner ◽  
Henrik Frederiksen ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Myeloproliferative Neoplasms ◽  
Modifier Genes ◽  
T Cell Lymphoma ◽  
Genomic Alterations ◽  
Specific Level ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Epigenetic Modifier ◽  
Tertiary Center

Background: Myeloproliferative neoplasia (MPN) and angioimmunoblastic T-cell lymphoma (AITL) are two distinct hematologic cancers. However, we have shown that patients with both malignancies probably occur with frequencies higher than expected in the background population (1,2). AITL tumors show a high frequency (30-70%) of mutations in RHOA and epigenetic modifier genes such as DNMT3A, TET2 and IDH2. The latter genomic alterations are similar to those found in myeloid diseases such as MPN. This observation has raised questions on whether the two hematologic malignancies may share genomic aberrations (e.g. at progenitor level) suggesting a possible pathogenetic relationship between these diseases. Aim: To further investigate these questions, we explored the mutational landscape in MPN and AITL tumors occurring in the same host. Methods: From a Danish cohort of 97 patients with co-existing MPN and lymphoma identified through the Danish Lymphoma and Pathology Registries and immunohistochemically validated by tertiary center hematopathologists, five patients with MPN and concurrent and/or subsequent AITL were included. Paired DNA samples obtained from lymph node biopsies (AITL component), bone marrow aspirates (MPN component) and saliva specimens (normal reference DNA) were analyzed by whole exome sequencing. A minimum variant allele frequency threshold of 10% was applied. However, mutations in epigenetic modifier genes, RHOA and JAK2, were also included, if found at slightly lower frequencies. Results: Figure 1 shows an overview of the identified mutations. At a VAF% cut-off value of 10 and a median coverage of 30, mutations shared between the MPN and AITL specimens were found within the DNMT3A, TET2, and IDH2 genes. Mutations in the JAK2 gene were identified in all MPN and in some of the AITL samples. NOTCH2 mutations were frequent and some were shared between the MPN and AITL samples. Two patients with essential thrombocytosis and AITL had the same NOTCH2 (C19W) and NCOR1 (K178N) mutation. Most of the identified genomic alterations were inactivating missense mutations. Conclusion: Co-existence of MPN and AITL occurs and may not be a random event. We studied tumor tissues from patients diagnosed with both diseases, and identified recurrent shared and non-shared mutations in samples from both types of cancers. These mutations may contribute to the development of the two malignancies in the same host, partly through common steps at precursor level (e.g. DNMT3A) and partly more downstream at a more lineage-specific level (e.g. IDH2). The functional role of the observed NOTCH2 and NCOR1 mutations is currently under investigation. Holst J et al. Blood 2017, 130 (S1): 1525 Frederiksen H et al. Blood 2011;118(25):6515-6520 Disclosures Tam: Takeda: Consultancy; Paragon Genomics: Consultancy.

Conformational characterization of nucleosome structure by Electron Microscopy

1993 ◽  
Vol 51 ◽  
pp. 194-195
Author(s):  
Gregory J. Czarnota
Keyword(s):  
Electron Microscopy ◽  
Structural Changes ◽  
Physiological State ◽  
Gene Activation ◽  
Three Dimensional ◽  
Macromolecular Complex ◽  
Ultrastructural Studies ◽  
Ionic Environment ◽  
Nucleosome Structure ◽  
Dimensional Reconstruction

Chromatin structure at the fundamental level of the nucleosome is important in vital cellular processes. Recent biochemical and genetic analyses show that nucleosome structure and structural changes are very active participants in gene expression, facilitating or inhibiting transcription and reflecting the physiological state of the cell. Structural states and transitions for this macromolecular complex, composed of DNA wound about a heterotypic octamer of variously modified histone proteins, have been measured by physico-chemical techniques and by enzyme-accessibility and are recognized to occur with various post-translational modifications, gene activation, transformation and with ionic-environment. In spite of studies which indicate various forms of nucleosome structure, all current x-ray and neutron diffraction studies have consistently resulted in only one structure, suggestive of a static conformation. In contrast, two-dimensional electron microscopy studies and three-dimensional reconstruction techniques have yielded different structures. These fundamental differences between EM and other ultrastructural studies have created a long standing quandary, which I have addressed and resolved using spectroscopic electron microscopy and statistical analyses of nucleosome images in a study of nucleosome structure with ionic environment.

GENE ACTIVATION IN MAMMARY CELLS

1972 ◽  
Vol 71 (2_Suppla) ◽  
pp. S346-S368 ◽  
Author(s):  
Roger W. Turkington ◽  
Nobuyuki Kadohama
Keyword(s):  
Cell Differentiation ◽  
Gene Transcription ◽  
Hormonal Regulation ◽  
Gene Activation ◽  
Milk Proteins ◽  
Mouse Mammary Gland ◽  
Nuclear Proteins ◽  
Mammary Cells ◽  
Alveolar Cells ◽  
Mammary Cell

ABSTRACT Hormonal activation of gene transcription has been studied in a model system, the mouse mammary gland in organ culture. Transcriptive activity is stimulated in mammary stem cells by insulin, and in mammary alveolar cells by prolactin and insulin. Studies on the template requirement for expression of the genes for milk proteins demonstrate that DNA methylation has an obligatory dependence upon DNA synthesis, but is otherwise independent from hormonal regulation of mammary cell differentiation. Incorporation of 5-bromo-2′deoxyuridine into DNA selectively inhibits expression of the genes for specific milk proteins. Undifferentiated mammary cells activate the synthesis of specific acidic nuclear proteins when stimulated by insulin. Several of these induced acidic nuclear proteins are undetectable in unstimulated undifferentiated cells, but appear to be characteristic components of the nuclei of differentiated cells. These results indicate that mammary cell differentiation is associated with a change in acidic nuclear proteins, and they provide evidence to support the concept that acidic nuclear proteins may be involved in the regulation of gene transcription and of mammary cell differentiation.

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