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3 results on '"Nowak, Daniel"'

1. In vivo deficiency of both C/EBPβ and C/EBPε results in highly defective myeloid differentiation and lack of cytokine response.

Author

Akagi, Tadayuki, Thoennissen, Nils H, George, Ann, Crooks, Gay, Song, Jee Hoon, Okamoto, Ryoko, Nowak, Daniel, Gombart, Adrian F, and Koeffler, H Phillip

Subjects
Neutrophils, Macrophages, Animals, Animals, Newborn, Mice, Knockout, Mice, Bacterial Infections, Lipopolysaccharides, CCAAT-Enhancer-Binding Proteins, CCAAT-Enhancer-Binding Protein-beta, Receptors, Immunologic, Cytokines, Blotting, Western, Oligonucleotide Array Sequence Analysis, Cluster Analysis, Gene Expression Profiling, Reverse Transcriptase Polymerase Chain Reaction, Cell Differentiation, Protein Binding, Female, Male, Gene Regulatory Networks, Interferon-gamma, Promoter Regions, Genetic, Mice, 129 Strain, Newborn, Blotting, Western, Strain, Knockout, Promoter Regions, Genetic, Receptors, Immunologic, General Science & Technology
Abstract

The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. Here, we generated C/EBPβ and C/EBPε double-knockout (bbee) mice and compared their phenotypes to those of single deficient (bbEE and BBee) and wild-type (BBEE) mice. The bbee mice were highly susceptible to fatal infections and died within 2-3 months. Morphologically, their neutrophils were blocked at the myelocytes/metamyelocytes stage, and clonogenic assays of bone marrow cells indicated a significant decrease in the number of myeloid colonies of the bbee mice. In addition, the proportion of hematopoietic progenitor cells [Lin(-)Sca1(+)c-Kit(+)] in the bone marrow of the bbee mice was significantly increased, reflecting the defective differentiation of the myeloid compartment. Furthermore, microarray expression analysis of LPS- and IFNγ-activated bone marrow-derived macrophages from bbee compared to single knockout mice revealed decreased expression of essential immune response-related genes and networks, including some direct C/EBP-targets such as Marco and Clec4e. Overall, the phenotype of the bbee mice is distinct from either the bbEE or BBee mice, demonstrating that both transcription factors are crucial for the maturation of neutrophils and macrophages, as well as the innate immune system, and can at least in part compensate for each other in the single knockout mice.

Published
2010

2. Increased separase activity and occurrence of centrosome aberrations concur with transformation of MDS

Author

Ruppenthal, Sabrina, Kleiner, Helga, Nolte, Florian, Fabarius, Alice, Hofmann, Wolf-Karsten, Nowak, Daniel, and Seifarth, Wolfgang

Subjects
Acute Myeloid Leukemia, Adult, Male, Centrosomes, lcsh:Medicine, Bone Marrow Cells, Apoptosis, Research and Analysis Methods, Hematologic Cancers and Related Disorders, Cytogenetics, Spectrum Analysis Techniques, Animal Cells, hemic and lymphatic diseases, Leukemias, Genetics, Medicine and Health Sciences, Humans, Cell Cycle and Cell Division, lcsh:Science, Separase, Aged, Aged, 80 and over, Centrosome, Chromosome Aberrations, Cell Death, Cell Cycle, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, Cell Biology, Hematology, Middle Aged, Myeloid Leukemia, Flow Cytometry, Phenotype, Oncology, Spectrophotometry, Cell Processes, Case-Control Studies, Karyotyping, Myelodysplastic Syndromes, Mutation, Female, lcsh:Q, Cytophotometry, Cellular Structures and Organelles, Karyotypes, Cellular Types, Research Article
Abstract

ESPL1/separase, a cysteine endopeptidase, is a key player in centrosome duplication and mitotic sister chromatid separation. Aberrant expression and/or altered separase proteolytic activity are associated with centrosome amplification, aneuploidy, tumorigenesis and disease progression. Since centrosome alterations are a common and early detectable feature in patients with myelodysplastic syndrome (MDS) and cytogenetic aberrations play an important role in disease risk stratification, we examined separase activity on single cell level in 67 bone marrow samples obtained from patients with MDS, secondary acute myeloid leukemia (sAML), de novo acute myeloid leukemia (AML) and healthy controls by a flow cytometric separase activity assay. The separase activity distribution (SAD) value, a calculated measure for the occurrence of cells with prominent separase activity within the analyzed sample, was tested for correlation with the centrosome, karyotype and gene mutation status. We found higher SAD values in bone marrow cells of sAML patients than in corresponding cells of MDS patients. This concurred with an increased incidence of aberrant centrosome phenotypes in sAML vs. MDS samples. No correlation was found between SAD values and the karyotype/gene mutation status. During follow-up of four MDS patients we observed increasing SAD values after transformation to sAML, in two patients SAD values decreased during azacitidine therapy. Cell culture experiments employing MDS-L cells as an in vitro model of MDS revealed that treatment with rigosertib, a PLK1 inhibitor and therapeutic drug known to induce G2/M arrest, results in decreased SAD values. In conclusion, the appearance of cells with unusual high separase activity levels, as indicated by increased SAD values, concurs with the transformation of MDS to sAML and may reflect separase dysregulation potentially contributing to clonal evolution during MDS progression. Separase activity measurement may therefore be useful as a novel additional molecular marker for disease monitoring.

Published
2018

3. In Vivo Deficiency of Both C/EBPβ and C/EBPϵ Results in Highly Defective Myeloid Differentiation and Lack of Cytokine Response.

Author

Akagi, Tadayuki, Thoennissen, Nils H., George, Ann, Crooks, Gay, Jee Hoon Song, Okamoto, Ryoko, Nowak, Daniel, Gombart, Adrian F., and Koeffler, H. Phillip

Subjects
TRANSCRIPTION factors, GENOTYPE-environment interaction, PHENOTYPES, HEMATOPOIETIC system, GENETICS, IMMUNE response, INFLAMMATORY mediators, BONE marrow cells, MACROPHAGES, MICE
Abstract

The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. Here, we generated C/EBPb and C/EBPe double-knockout (bbee) mice and compared their phenotypes to those of single deficient (bbEE and BBee) and wild-type (BBEE) mice. The bbee mice were highly susceptible to fatal infections and died within 2-3 months. Morphologically, their neutrophils were blocked at the myelocytes/metamyelocytes stage, and clonogenic assays of bone marrow cells indicated a significant decrease in the number of myeloid colonies of the bbee mice. In addition, the proportion of hematopoietic progenitor cells [Lin(2)Sca1(+)c-Kit(+)] in the bone marrow of the bbee mice was significantly increased, reflecting the defective differentiation of the myeloid compartment. Furthermore, microarray expression analysis of LPS- and IFNc-activated bone marrow-derived macrophages from bbee compared to single knockout mice revealed decreased expression of essential immune response-related genes and networks, including some direct C/EBP-targets such as Marco and Clec4e. Overall, the phenotype of the bbee mice is distinct from either the bbEE or BBee mice, demonstrating that both transcription factors are crucial for the maturation of neutrophils and macrophages, as well as the innate immune system, and can at least in part compensate for each other in the single knockout mice. [ABSTRACT FROM AUTHOR]

Published
2010
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