Stem Cell Research

Quiescent Hematopoietic Stem Cells Accumulate DNA Damage during Aging that Is Repaired upon Entry into Cell Cycle

“…Moreover, it seems likely that the attenuation of DNA repair and response pathways we observe in quiescent HSCs, could lead to age-associated mutation accrual beyond strand breaks. Indeed, the idea that HSCs serve as the primary reservoir for mutation accrual underlying the development of diverse age-associated hematopoietic diseases such a MDS and AML is now widely accepted (Jan et al, 2012; Krivtsov et al, 2013; Rossi et al, 2007a; Shlush et al, 2014; Taussig et al, 2005; Tehranchi et al, 2010; Weissman, 2005; Will et al, 2012) Our data demonstrating that HSC quiescence and concomitant attenuation of DNA repair and response pathways provides a mechanism through which such premalignant mutations in HSCs may accrue. It should be stated that other adult stem cell tissue systems such as brain, gastrointestinal tract, skin, etc., will very likely follow the same energy saving paradigm- and accumulate DNA damage in quiescent stem cells, and repair these insults when it is necessary to enter cell cycle.…”

Evolution of normal and neoplastic tissue stem cells: progress after Robert Hooke

“…The particular breakpoint of the translocation produced a clonal tracer for that leukaemia, and in every case, the MPP-LSC translocation was found in otherwise normal HSCs in the same patient, and at a frequency that could only be explained by expansion from a single cell to hundreds of thousands of 'preleukaemia' cells [49]. This clearly implied that normal HSCs harboured the initiating event and were expanding, but that more events would be required before the preleukaemic and marked HSCs could give rise to the leukaemic MPP-LSC [48]. What we did not realize is that the preleukaemic stem cells were expanding at the expense of normal HSCs, not adding to normal HSCs.…”

Molecular Signatures of Quiescent, Mobilized and Leukemia-Initiating Hematopoietic Stem Cells

“…Recent evidence indicates that LSC can emerge either from transformed HSC [17], [18] or from transformed progenitor cells that have re-acquired the stem cell property of self-renewal [15]. In one model, preleukemic progression of a myeloproliferative disorder occurs in the only self-renewing cells of the myeloid lineage, HSC, but emerges from these clones when self-renewal is not shut down [or re-emerges] when these preleukemic or chronic phase leukemic HSC develop multipotent or oligolineage progenitors at acute or blast crisis phases of the disease [19]. Developing interventions that specifically target LSC is an appealing strategy for improving the specificity and efficiency of cancer treatment [20].…”