Granulocyte maturation determines ability to release chromatin NETs and loss of DNA damage response; these properties are absent in immature AML granulocytes
Language English Country Netherlands Media print-electronic
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
23269287
DOI
10.1016/j.bbamcr.2012.12.012
PII: S0167-4889(12)00390-4
Knihovny.cz E-resources
- MeSH
- Leukemia, Myeloid, Acute genetics metabolism pathology MeSH
- Cell Differentiation * MeSH
- Chromatin genetics MeSH
- Chromosomal Proteins, Non-Histone genetics metabolism MeSH
- Fluorescent Antibody Technique MeSH
- Granulocytes metabolism pathology MeSH
- Hematopoietic Stem Cells metabolism pathology MeSH
- Chromobox Protein Homolog 5 MeSH
- Cells, Cultured MeSH
- Real-Time Polymerase Chain Reaction MeSH
- Humans MeSH
- RNA, Messenger genetics MeSH
- Neutrophils pathology MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- DNA Damage * MeSH
- Cell Proliferation MeSH
- Tetradecanoylphorbol Acetate MeSH
- Blotting, Western MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- CBX1 protein, human MeSH Browser
- Chromatin MeSH
- Chromosomal Proteins, Non-Histone MeSH
- Chromobox Protein Homolog 5 MeSH
- RNA, Messenger MeSH
- Tetradecanoylphorbol Acetate MeSH
Terminally-differentiated cells cease to proliferate and acquire specific sets of expressed genes and functions distinguishing them from less differentiated and cancer cells. Mature granulocytes show lobular structure of cell nuclei with highly condensed chromatin in which HP1 proteins are replaced by MNEI. These structural features of chromatin correspond to low level of gene expression and the loss of some important functions as DNA damage repair, shown in this work and, on the other hand, acquisition of a new specific function consisting in the release of chromatin extracellular traps in response to infection by pathogenic microbes. Granulocytic differentiation is incomplete in myeloid leukemia and is manifested by persistence of lower levels of HP1γ and HP1β isoforms. This immaturity is accompanied by acquisition of DDR capacity allowing to these incompletely differentiated multi-lobed neutrophils of AML patients to respond to induction of DSB by γ-irradiation. Immature granulocytes persist frequently in blood of treated AML patients in remission. These granulocytes contrary to mature ones do not release chromatin for NETs after activation with phorbol myristate-12 acetate-13 and do not exert the neutrophil function in immune defence. We suggest therefore the detection of HP1 expression in granulocytes of AML patients as a very sensitive indicator of their maturation and functionality after the treatment. Our results show that the changes in chromatin structure underlie a major transition in functioning of the genome in immature granulocytes. They show further that leukemia stem cells can differentiate ex vivo to mature granulocytes despite carrying the translocation BCR/ABL.
References provided by Crossref.org
Spatial-Temporal Genome Regulation in Stress-Response and Cell-Fate Change
