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Tremblay, Cedric S; Saw, Jesslyn; Chiu, Sung Kai; Wong, Nicholas C; Tsyganov, Kirill; Ghotb, Sarah; Graham, Alison N; Yan, Feng; Guirguis, Andrew A; Sonderegger, Stefan E; Lee, Nicole; Kalitsis, Paul; Reynolds, John; Ting, Stephen B; Powell, David R; Jane, Stephen M; Curtis, David J
Nature communications, 08/2018, Volume: 9, Issue: 1Journal Article
Pre-leukemic stem cells (pre-LSCs) give rise to leukemic stem cells through acquisition of additional gene mutations and are an important source of relapse following chemotherapy. We postulated that cell-cycle kinetics of pre-LSCs may be an important determinant of clonal evolution and therapeutic resistance. Using a doxycycline-inducible H2B-GFP transgene in a mouse model of T-cell acute lymphoblastic leukemia to study cell cycle in vivo, we show that self-renewal, clonal evolution and therapeutic resistance are limited to a rare population of pre-LSCs with restricted cell cycle. We show that proliferative pre-LSCs are unable to return to a cell cycle-restricted state. Cell cycle-restricted pre-LSCs have activation of p53 and its downstream cell-cycle inhibitor p21. Furthermore, absence of p21 leads to proliferation of pre-LSCs, with clonal extinction through loss of asymmetric cell division and terminal differentiation. Thus, inducing proliferation of pre-LSCs represents a promising strategy to increase cure rates for acute leukemia.
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