Bone Marrow Senescence and the Microenvironment of Hematological Malignancies

Charlotte Hellmich, Jamie A Moore, Kristian M Bowles, Stuart A Rushworth, Charlotte Hellmich, Jamie A Moore, Kristian M Bowles, Stuart A Rushworth

Abstract

Senescence is the irreversible arrest of cell proliferation that has now been shown to play an important role in both health and disease. With increasing age senescent cells accumulate throughout the body, including the bone marrow and this has been associated with a number of age-related pathologies including malignancies. It has been shown that the senescence associated secretory phenotype (SASP) creates a pro-tumoural environment that supports proliferation and survival of malignant cells. Understanding the role of senescent cells in tumor development better may help us to identify new treatment targets to impair tumor survival and reduce treatment resistance. In this review, we will specifically discuss the role of senescence in the aging bone marrow (BM) microenvironment. Many BM disorders are age-related diseases and highly dependent on the BM microenvironment. Despite advances in drug development the prognosis particularly for older patients remains poor and new treatment approaches are needed to improve outcomes for patients. In this review, we will focus on the relationship of senescence and hematological malignancies, how senescence promotes cancer development and how malignant cells induce senescence.

Keywords: SASP; cancer microenvironment; leukemia; p16INK4a; senescence.

Copyright © 2020 Hellmich, Moore, Bowles and Rushworth.

Figures

Figure 1
Figure 1
(A,B) The desired and adverse effect of cytotoxic chemotherapy. By inducing senescence in the malignant cell these treatments inhibit cell proliferation and promote clearance of senescent cells through activation of the immune system. Conversely when a senescent phenotype occurs within the tumor microenvironment this can promote chronic inflammation, tumor growth and it can impair normal bone marrow function.
Figure 2
Figure 2
The exact relationship between the senescent phenotype in the BM microenvironment and tumorigenesis remains to be established. We propose three possible pathways by which the senescent pro-tumoral BM microenvironment is created: (A) The senescent process is driven by normal aging and external factors and this creates an environment in which clonal hematopoiesis and tumorigenesis is favored. (B) The clonally expanding cell populations are the primary drivers of senescence in the BM microenvironment. (C) These two processes occur in parallel, impact on each other to varying degrees and together drive the observed changes in the BM.

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