Trends in Molecular Medicine
Feature ReviewLosing Sense of Self and Surroundings: Hematopoietic Stem Cell Aging and Leukemic Transformation
Section snippets
The Connection between Aging and Cancer in the Hematopoietic System
HSCs are responsible for the life-long maintenance of blood production. With age, HSCs lose their regenerative capacity, leading to typical features of blood aging, including immunosenescence, anemia, and unbalanced myeloid cell production 1., 2.. These features, in turn, drive an increased risk of autoimmunity and hematological malignancies [3]. In this perspective, we review drivers of age-associated HSC dysfunction and their potential contribution to HSC clonal expansion (see Glossary) and
Hallmarks of Aged HSCs
The hematopoietic system faces tremendous demands to produce 1011–1012 mature cells per day in humans, satisfied by a small population of BM-resident HSCs. Our understanding of HSC biology is mainly based on studies in mice, and unless indicated these reports are the primary focus of the present review. HSCs are defined by their ability to self-renew to maintain lifelong potential and to differentiate to produce all lineages of the blood and immune systems [4]. In mice, this is demonstrated
Metabolic Derangement and Epigenetic Drift as the Basis of Cell-Intrinsic HSC Aging
Metabolism and epigenetics are tightly linked in their regulation of HSC function [19] and are significantly affected by aging. The cellular features of HSC dysfunction in aging primarily manifest as a failure to maintain appropriate mitochondrial and metabolic regulation 19., 20., 21. (Figure 1). In this section, we review the basis of the metabolic and epigenetic control of HSC function, provide an overview of how these mechanisms are perturbed over the course of aging, and finally discuss
Deteriorating HSC Niche as Driver of Aging and Blood Cancer
While the majority of studies on HSC aging and transformation focus on intrinsic changes, the BM niche where HSCs reside also contributes to these processes (Figure 3). In this section, we review the role of the BM niche in HSC function, provide an overview of the changes in the BM microenvironment occurring during aging, and finally summarize how functional alterations of the niche can contribute to the development and propagation of leukemia.
ARCH and Preleukemic Disposition in Humans
In humans, aging is frequently accompanied by the development of clonal hematopoiesis, in approximately 10% of individuals greater than 70 years old 128., 129.. The full extent of the clinical relevance of ARCH was realized only recently, when copy number variation (CNV) and next-generation sequencing analysis demonstrated that ARCH is characterized by the presence of leukemia-associated mutations in expanded, nonleukemic clones of blood cells in the elderly 130., 131., 132.. Clonal expansion
New Insights into the Rational Design of Antiaging Interventions
Metabolism, epigenetics, and niche-mediated inflammatory signaling pathways have emerged as critical interrelated determinants of HSC aging and leukemic transformation. Several approaches aimed at restoring the metabolic and epigenetic profiles of old HSCs, and rebuilding the supportive activity of or blocking inflammatory signals from the BM microenvironment, have been recently described in mouse models of aging. Overexpression of Sirt3 [10] and Sirt7 [9] or treatment with the mTOR inhibitor
Concluding Remarks and Future Perspectives
The identification of epigenetic drift and metabolic activation as drivers of cell-intrinsic HSC aging and leukemic transformation opens exciting new therapeutic routes to restore hematopoietic function. The role of the deteriorating BM microenvironment in promoting HSC dysfunction in aging, and the dependence of LSCs on a perturbed BM niche, open complementary avenues. Future research (see Outstanding Questions) should focus on developing an integrated perspective on the complex interplay of
Clinician’s Corner
Aging interventions need to hit clinically tangible endpoints to be pragmatically translated.
Mutations in epigenetic readers in age-related clonal hematopoiesis are frequent initiating events that support clonal competition and preneoplastic stem cells 128., 158., suggesting that epigenetic deregulation is one of the central promoters of leukemic transformation.
Recent evidence suggests that targeting metabolic cofactors such as ascorbate can influence the epigenetic poising of HSCs and allow
Outstanding Questions
How are different features of cell-intrinsic HSC aging interrelated? Which features are rate limiting in HSC functional decline?
What comes first: the aging of the BM microenvironment/inflammation or intrinsic changes in the hematopoietic system, in particular HSCs?
Is aging of the hematopoietic system reversible or preventable? If yes, at which age should interventions be targeted?
How representative are mouse models of hematopoietic aging or leukemia development? Should further modeling be
Acknowledgments
E.V.V. is supported by a Rubicon Grant from The Netherlands Organisation for Scientific Research, a Stem Cell Grant from BD Biosciences, and the Empire State Stem Cell Fund through New York State Department of Health Contract #DOH01-C30291GG-3450000 to Columbia University. This work was supported by an NIH 1R35HL135763 grant and LLS Scholar Award to E.P.
Glossary
- Additional sex combs-like transcriptional regulator 1 (ASXL1)
- a protein associated with PRCs that maintains the methylation of histone H3K27, an important repressive histone mark.
- Age-related clonal hematopoiesis (ARCH)
- expansion of clones that acquired fitness advantage as a result of mutation that is observed in older individuals; 90% of ARCH mutations occur in enzymes involved in the regulation of epigenetics and metabolism, including TET2, DNMT3A, and ASXL1. ARCH-associated mutations are also
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These authors contributed equally to this work