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

Cedric Tremblay, Jesslyn Saw, Sung Kai Chiu, Nicholas C. Wong, Kirill Tsyganov, Sarah Ghotb, Alison N Graham, Feng Yan, Andrew Guirguis, Stefan Sonderegger, Nicole Lee, Paul Kalitsis, John Reynolds, Stephen Ting, David Powell, Stephen Jane, David Curtis

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number3535
Number of pages13
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Tremblay, Cedric ; Saw, Jesslyn ; Chiu, Sung Kai ; Wong, Nicholas C. ; Tsyganov, Kirill ; Ghotb, Sarah ; Graham, Alison N ; Yan, Feng ; Guirguis, Andrew ; Sonderegger, Stefan ; Lee, Nicole ; Kalitsis, Paul ; Reynolds, John ; Ting, Stephen ; Powell, David ; Jane, Stephen ; Curtis, David. / Restricted cell cycle is essential for clonal evolution and therapeutic resistance of pre-leukemic stem cells. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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.",
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Restricted cell cycle is essential for clonal evolution and therapeutic resistance of pre-leukemic stem cells. / Tremblay, Cedric; Saw, Jesslyn; Chiu, Sung Kai; Wong, Nicholas C.; Tsyganov, Kirill; Ghotb, Sarah; Graham, Alison N; Yan, Feng; Guirguis, Andrew; Sonderegger, Stefan; Lee, Nicole; Kalitsis, Paul; Reynolds, John; Ting, Stephen; Powell, David; Jane, Stephen; Curtis, David.

In: Nature Communications, Vol. 9, No. 1, 3535, 01.12.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Tremblay, Cedric

AU - Saw, Jesslyn

AU - Chiu, Sung Kai

AU - Wong, Nicholas C.

AU - Tsyganov, Kirill

AU - Ghotb, Sarah

AU - Graham, Alison N

AU - Yan, Feng

AU - Guirguis, Andrew

AU - Sonderegger, Stefan

AU - Lee, Nicole

AU - Kalitsis, Paul

AU - Reynolds, John

AU - Ting, Stephen

AU - Powell, David

AU - Jane, Stephen

AU - Curtis, David

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