Epigenetic Changes as a Target in Aging Haematopoietic Stem Cells and Age-Related Malignancies

摘要

Aging is associated with multiple molecular and functional changes in haematopoietic cells. Most notably, the self-renewal and differentiation potential of hematopoietic stem cells (HSCs) are compromised, resulting in myeloid skewing, reduced output of red blood cells and decreased generation of immune cells. These changes result in anaemia, increased susceptibility for infections and higher prevalence of haematopoietic malignancies. In HSCs, age-associated global epigenetic changes have been identified. These epigenetic alterations in aged HSCs can occur randomly (epigenetic drift) or are the result of somatic mutations in genes encoding for epigenetic proteins. Mutations in loci that encode epigenetic modifiers occur frequently in patients with haematological malignancies, but also in healthy elderly individuals at risk to develop these. It may be possible to pharmacologically intervene in the aberrant epigenetic program of derailed HSCs to enforce normal haematopoiesis or treat age-related haematopoietic diseases. Over the past decade our molecular understanding of epigenetic regulation has rapidly increased and drugs targeting epigenetic modifications are increasingly part of treatment protocols. The reversibility of epigenetic modifications renders these targets for novel therapeutics. In this review we provide an overview of epigenetic changes that occur in aging HSCs and age-related malignancies and discuss related epigenetic drugs.