Feature Review
Losing Sense of Self and Surroundings: Hematopoietic Stem Cell Aging and Leukemic Transformation

https://doi.org/10.1016/j.molmed.2019.04.006Get rights and content

Highlights

  • Metabolic activation and epigenetic alterations emerge as major contributors to the decline of hematopoietic stem cell (HSC) function with age. It has also become evident that epigenetic and metabolic regulation of HSCs are tightly linked.

  • Recent data provide new insights into the role of the bone marrow niche microenvironment in regulating HSC function. In particular, the role of the inflammatory microenvironment in enforcing the preferential transformation and survival of mutation-bearing clones has emerged during aging and leukemogenesis.

  • Mutations in epigenetic modifier and metabolic genes are associated with age-related clonal hematopoiesis (ARCH). Specific mutational signatures of ARCH can predict leukemia onset years before diagnosis and ARCH has been found associated with a range of nonhematopoietic morbidities and high mortality.

  • Restoration of metabolic and epigenetic profiles and blocking of inflammatory signaling have been shown to be prime targets for the rejuvenation of aged HSCs and prevention of leukemic transformation.

Aging leads to functional decline of the hematopoietic system, manifested by an increased incidence of hematological disease in the elderly. Deterioration of hematopoietic integrity with age originates in part from the degraded functionality of hematopoietic stem cells (HSCs). Here, we review recent findings identifying changes in metabolic programs and loss of epigenetic identity as major drivers of old HSC dysfunction and their role in promoting leukemia onset in the context of age-related clonal hematopoiesis (ARCH). We discuss how inflammatory and growth signals from the aged bone marrow (BM) microenvironment contribute to cell-intrinsic HSC aging phenotypes and favor leukemia development. Finally, we address how metabolic, epigenetic, and inflammatory pathways could be targeted to enhance old HSC fitness and prevent 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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