Restricted cell cycle is essential for clonal evolution and therapeutic resistance of pre-leukemic stem cells
In: Nature Communications, Jg. 9 (2018), Heft 1, S. 1-13
Online
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Zugriff:
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.
Cell cycle kinetics of pre-leukemic stem cells (pre-LSCs) may be an important determinant of clonal evolution and therapeutic resistance. Here, the AUs use a transgenic T-ALL mouse model that allows non-dividing cells to be tracked and identify a subset of non-dividing pre-LSCs maintained by p21.
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Restricted cell cycle is essential for clonal evolution and therapeutic resistance of pre-leukemic stem cells
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Autor/in / Beteiligte Person: | Wong, Nicholas C. ; Tremblay, Cedric S. ; Tsyganov, Kirill ; Jane, Stephen M. ; Guirguis, Andrew A. ; Sung Kai Chiu ; Ting, Stephen B. ; Graham, Alison N. ; Curtis, David J. ; Reynolds, John V. ; Stefan Eugen Sonderegger ; Powell, David R. ; Yan, Feng ; Kalitsis, Paul ; Lee, Nicole K. ; Ghotb, Sarah ; Saw, Jesslyn |
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Zeitschrift: | Nature Communications, Jg. 9 (2018), Heft 1, S. 1-13 |
Veröffentlichung: | Nature Publishing Group, 2018 |
Medientyp: | unknown |
ISSN: | 2041-1723 (print) |
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