Abstract
Simple SummarySenescence is a cellular program in response to stress and can prevent the expansion of pre-malignant and malignant cells by cell cycle arrest. However, long-term pro-tumorigenic effects have been described. This review aims to compile molecular mechanisms of cellular senescence and to discuss potential therapeutic implications in myeloid malignancies.Senescence is a cellular state that is involved in aging-associated diseases but may also prohibit the development of pre-cancerous lesions and tumor growth. Senescent cells are actively secreting chemo- and cytokines, and this senescence-associated secretory phenotype (SASP) can contribute to both early anti-tumorigenic and long-term pro-tumorigenic effects. Recently, complex mechanisms of cellular senescence and their influence on cellular processes have been defined in more detail and, therefore, facilitate translational development of targeted therapies. In this review, we aim to discuss major molecular pathways involved in cellular senescence and potential therapeutic strategies, with a specific focus on myeloid malignancies.
Highlights
Introduction on Cellular SenescenceThe inability of somatic mammalian cells to undergo further replication was first described as cellular senescence in 1961 [1]
Regarding AML biology, an miR-34c-5p deficiency was found in leukemia stem cells (LSC) of AML patients when compared to normal hematopoietic stem cells (HSC) and has been associated with poor prognosis [42]
Considerable progress has been made in understanding the molecular regulatory mechanisms of senescence and its biological function in tissue aging and tumorigenesis, which appears to be highly dependent on cell type
Summary
The inability of somatic mammalian cells to undergo further replication was first described as cellular senescence in 1961 [1]. Replicative senescence state cells can develop so-called premature senescence independent of their biologic or in vitro culture age This state can be induced by oncogenes, including Ras and factors that cause DNA damage, such as oxidative stress, alcohol, and bacterial lipopolysaccharides [10,11,12,13]. By local changes in chromatin structure, γH2AX leads to recruiting the DNA repair complex with a focal assembly of the checkpoint kinases CHK1 and CHK2, which can be phosphorylated by ATR and ATM Both ATM and phosphorylated CHK2 at Threonine 68 are able to activate p53 by phosphorylation, which leads to the induction of cell cycle arrest [30]. While the ATM-CHK2 axis plays an auxiliary role, especially in response to DSB, the ATR-CHK1 axis is the main effector of DNA damage and replication control points [31]
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