Journal article

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, David J Curtis

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2018

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..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Funding Acknowledgements

We thank Geza Paukovics, Jeanne LeMasurier, Eva Orlowski-Oliver and Phil Donaldson from the AMREP Flow Cytometry Facility for assistance with flow cytometry. We also thank Stephen Cody and Iska Carmichael from the Monash Micro Imaging platform as well as Shilpa Bereeka and Loretta Cerruti for technical assistance. We thank Associate Professor Steven Lane from the QIMR Berghofer, Professor Sarah Russell and Dr Mirren Charnley from the Peter MacCallum Cancer Centre and the Centre for Micro-Photonics of the Swinburne University of Technology, as well as Dr Ian Majewski and Dr Kim Pham from the Walter and Eliza Hall Institute for Medical Research (WEHI) for assistance with experimental design and intellectual input. This work was supported by Project Grants (1052313 (to D.J.C.), 1047554 (to S.B.T.)) and a Career Development Fellowship (1047630 (to S.B.T.)) from the Australian National Health and Medical Research Council (NHMRC), and a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Foundation (to D.J.C.).