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Restricted cell cycle is essential for clonal evolution and therapeutic resistance of pre-leukemic stem cells.

Nature communications (2018-09-01)
Cedric S Tremblay, Jesslyn Saw, Sung Kai Chiu, Nicholas C Wong, Kirill Tsyganov, Sarah Ghotb, Alison N Graham, Feng Yan, Andrew A Guirguis, Stefan E Sonderegger, Nicole Lee, Paul Kalitsis, John Reynolds, Stephen B Ting, David R Powell, Stephen M Jane, David J Curtis
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Mowiol® 4-88, Mw ~31,000
Sigma-Aldrich
7-Aminoactinomycin D, ~97% (HPLC), powder

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