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SIRT7: an influence factor in healthy aging and the development of age-dependent myeloid stem-cell disorders

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Title: SIRT7: an influence factor in healthy aging and the development of age-dependent myeloid stem-cell disorders
Authors: Alexander Kaiser, Martin Schmidt, Otmar Huber, Jochen J. Frietsch, Sebastian Scholl, Florian H. Heidel, Andreas Hochhaus, Jörg P. Müller, Thomas Ernst
Source: Leukemia
Publisher Information: Springer Science and Business Media LLC, 2020.
Publication Year: 2020
Subject Terms: Age Factors [MeSH], Mutation [MeSH], Aged, 80 and over [MeSH], Leukaemia, CCAAT-Enhancer-Binding Protein-alpha/metabolism [MeSH], Aged [MeSH], Leukemia, Myeloid, Acute/etiology [MeSH], Adult [MeSH], Humans [MeSH], Fusion Proteins, bcr-abl/antagonists, Middle Aged [MeSH], Cell Differentiation [MeSH], THP-1 Cells [MeSH], Sirtuins/physiology [MeSH], Article, Sirtuins/genetics [MeSH], fms-Like Tyrosine Kinase 3/genetics [MeSH], Leukemia, Myeloid, Acute/drug therapy [MeSH], Cancer stem cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy [MeSH], Leukemia, Myelogenous, Chronic, BCR-ABL Positive/etiology [MeSH], Healthy Aging [MeSH], Adult, Aged, 80 and over, 0301 basic medicine, 0303 health sciences, THP-1 Cells, Age Factors, Fusion Proteins, bcr-abl, Cell Differentiation, Middle Aged, 3. Good health, Healthy Aging, Leukemia, Myeloid, Acute, 03 medical and health sciences, fms-Like Tyrosine Kinase 3, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mutation, CCAAT-Enhancer-Binding Protein-alpha, Humans, Sirtuins, Aged
Description: Molecular alterations within the hematopoietic system influence cellular longevity and development of age-related myeloid stem-cell disorders like acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). A reduced SIRT7-expression in aged murine hematopoietic stem cells (HSC) resulted in reduced longevity and increased proliferation. In this study we investigated age-related changes of SIRT7-expression in healthy humans and relevant pathomechanisms in AML and CML. SIRT7-expression in leukocytes of healthy people decreased in an age-dependent manner. Low SIRT7 mRNA levels were also detected in AML and CML patients. With positive treatment response, SIRT7-expression increased, but showed reduction when patients progressed or relapsed. Pharmacologic inhibition of driver mutations in AML (FLT3-ITD) or CML (BCR-ABL) also restored SIRT7 levels in cell lines and patient samples. Furthermore, SIRT7-expression increased with time during PMA-mediated monocyte differentiation of THP-1 cells. SIRT7-overexpression in THP-1 cells resulted in increased expression of differentiation markers. BCR-ABL, FLT3-ITD, and differentiation-associated SIRT7-expression in general were positively regulated by C/EBPα, -β, and -ε binding to two different C/EBP-binding sites within the SIRT7 promoter. SIRT7 is important in human hematopoietic cell aging and longevity. It might act as tumor suppressor and could potentially serve as general biomarker for monitoring treatment response in myeloid stem-cell disorders.
Document Type: Article
Other literature type
Language: English
ISSN: 1476-5551
0887-6924
DOI: 10.1038/s41375-020-0803-3
Access URL: https://pubmed.ncbi.nlm.nih.gov/32214204
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318878
https://www.nature.com/articles/s41375-020-0803-3.pdf
https://www.scilit.net/article/bc17857702b27532cb37fc872219ead4?action=show-references
https://www.ncbi.nlm.nih.gov/pubmed/32214204
https://www.nature.com/articles/s41375-020-0803-3
https://pubmed.ncbi.nlm.nih.gov/32214204/
https://repository.publisso.de/resource/frl:6471052
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) .
Accession Number: edsair.doi.dedup.....6f81e4875b43ffd6afeb55ee79bad595
Database: OpenAIRE
Description
Abstract:Molecular alterations within the hematopoietic system influence cellular longevity and development of age-related myeloid stem-cell disorders like acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). A reduced SIRT7-expression in aged murine hematopoietic stem cells (HSC) resulted in reduced longevity and increased proliferation. In this study we investigated age-related changes of SIRT7-expression in healthy humans and relevant pathomechanisms in AML and CML. SIRT7-expression in leukocytes of healthy people decreased in an age-dependent manner. Low SIRT7 mRNA levels were also detected in AML and CML patients. With positive treatment response, SIRT7-expression increased, but showed reduction when patients progressed or relapsed. Pharmacologic inhibition of driver mutations in AML (FLT3-ITD) or CML (BCR-ABL) also restored SIRT7 levels in cell lines and patient samples. Furthermore, SIRT7-expression increased with time during PMA-mediated monocyte differentiation of THP-1 cells. SIRT7-overexpression in THP-1 cells resulted in increased expression of differentiation markers. BCR-ABL, FLT3-ITD, and differentiation-associated SIRT7-expression in general were positively regulated by C/EBPα, -β, and -ε binding to two different C/EBP-binding sites within the SIRT7 promoter. SIRT7 is important in human hematopoietic cell aging and longevity. It might act as tumor suppressor and could potentially serve as general biomarker for monitoring treatment response in myeloid stem-cell disorders.
ISSN:14765551
08876924
DOI:10.1038/s41375-020-0803-3