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

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 and David J. Curtis ()
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Cedric S. Tremblay: Monash University
Jesslyn Saw: Monash University
Sung Kai Chiu: Monash University
Nicholas C. Wong: Monash University
Kirill Tsyganov: Monash University
Sarah Ghotb: Monash University
Alison N. Graham: Royal Children’s Hospital
Feng Yan: Monash University
Andrew A. Guirguis: Monash University
Stefan E. Sonderegger: Monash University
Nicole Lee: Monash University
Paul Kalitsis: Royal Children’s Hospital
John Reynolds: Monash University
Stephen B. Ting: Monash University
David R. Powell: Monash University
Stephen M. Jane: Alfred Hospital
David J. Curtis: Monash University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06021-7

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