Quiescence regulation by normal haematopoietic stem cells and leukaemia stem cells

The haematopoietic system is maintained by rare haematopoietic stem cells (HSCs), which are quiescent most of the time and only divide occasionally to self-renew and/or to undergo commitment to clonal expansion via the generation of highly proliferative progenitor cells. The latter is responsible for the generation of all mature cells of the system through subsequent lineage commitment and terminal differentiation. Cells with similar properties also exist in leukaemias and are known as leukaemia stem cells (LSCs). Quiescence provides essential protection for both HSC and LSC from cytotoxic stress and DNA damage and, in the case of LSCs, likely causes therapy resistance and disease relapse in leukaemia patients. Specific inhibition of LSC quiescence has been considered a promising strategy for eliminating LSCs and curing leukaemias. Although the understanding of mechanisms responsible for quiescence maintenance in these cells remains limited, particularly for LSCs, recent studies have suggested potential differences in their dependency on certain pathways and their levels of stress and DNA damage caused by increased cycling. Such differences likely stem from oncogenic mutations in LSCs and could be specifically exploited for the elimination of LSCs while sparing normal HSCs in the future.