Overcoming quiescence by targeting p21 (Cdkn1a) sensitizes pre-leukemic stem cells to chemotherapy

Cedric Tremblay, Jesslyn Mei Yoong Saw, Sung Kai Chiu, David John Curtis

Research output: Contribution to conferenceAbstractOtherpeer-review

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous malignancy, with 1 out of 5 patients dying from refractory disease. Recent studies support the concept that cells responsible for relapse frequently develop from a small population of quiescent pre-leukemic stem cells (pre-LSCs) that give rise to clonal heterogeneity. Using the Lmo2 transgenic mouse model, we have shown previously that these pre-LSCs have long-term self-renewal potential and resistance to high dose radiation. To determine if quiescence is an important property of pre-LSCs, we first used the doxycycline inducible H2B-GFP transgenic mouse model to show the existence of rare (<1%) pre-LSCs that cycle less than once a month in Lmo2 transgenic mice. Importantly, radiation therapy lead to a 5-fold enrichment of these rare pre-LSCs, confirming that quiescence protects pre-LSCs from genotoxic stress. We then used mice lacking the cell cycle regulator Cdkn1a (p21) to address the importance of quiescence in therapeutic resistance. Absence of p21 had no effect on the formation of pre-LSCs but reduced the proportion of quiescent pre-LSCs in vivo. Importantly, pre-LSCs lacking p21 were sensitive to killing by radiation therapy and chemotherapy. Finally, we aged cohorts of mice to determine the role of p21 in the clonal evolution of pre-LSCs. Remarkably, absence of p21 strongly impaired the clonal selection of pre-LSCs and the subsequent development of T-ALL. Gene expression analysis revealed that absence of p21 was associated with reduced expression of quiescence and increased expression of T-cell differentiation genes in pre-LSCs. The restored differentiation profile in Lmo2 mice lacking p21 together with these gene expression profiles indicate that loss of p21 triggers differentiation of pre-LSCs. These results provide the most convincing in vivo evidence that p21 is required for the quiescence, maintenance, clonal evolution and therapeutic resistance of pre-LSCs. Targeting p21 and other regulators of quiescence may represent a promising new therapeutic strategy for improving cure rates in T-ALL.
Original languageEnglish
PagesS45
Number of pages1
Publication statusPublished - 1 Sep 2015
EventISEH 44th Annual Scientific Meeting: International Society for Experimental Hematology - Kyoto International Conference Center, Kyoto, Japan
Duration: 17 Sep 201519 Sep 2015
Conference number: 44
http://www.iseh.org/events/EventDetails.aspx?id=503256

Conference

ConferenceISEH 44th Annual Scientific Meeting
Abbreviated title44th Annual Scientific Meeting of the ISEH
CountryJapan
CityKyoto
Period17/09/1519/09/15
Internet address

Cite this

Tremblay, C., Saw, J. M. Y., Chiu, S. K., & Curtis, D. J. (2015). Overcoming quiescence by targeting p21 (Cdkn1a) sensitizes pre-leukemic stem cells to chemotherapy. S45. Abstract from ISEH 44th Annual Scientific Meeting, Kyoto, Japan.
Tremblay, Cedric ; Saw, Jesslyn Mei Yoong ; Chiu, Sung Kai ; Curtis, David John. / Overcoming quiescence by targeting p21 (Cdkn1a) sensitizes pre-leukemic stem cells to chemotherapy. Abstract from ISEH 44th Annual Scientific Meeting, Kyoto, Japan.1 p.
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title = "Overcoming quiescence by targeting p21 (Cdkn1a) sensitizes pre-leukemic stem cells to chemotherapy",
abstract = "T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous malignancy, with 1 out of 5 patients dying from refractory disease. Recent studies support the concept that cells responsible for relapse frequently develop from a small population of quiescent pre-leukemic stem cells (pre-LSCs) that give rise to clonal heterogeneity. Using the Lmo2 transgenic mouse model, we have shown previously that these pre-LSCs have long-term self-renewal potential and resistance to high dose radiation. To determine if quiescence is an important property of pre-LSCs, we first used the doxycycline inducible H2B-GFP transgenic mouse model to show the existence of rare (<1{\%}) pre-LSCs that cycle less than once a month in Lmo2 transgenic mice. Importantly, radiation therapy lead to a 5-fold enrichment of these rare pre-LSCs, confirming that quiescence protects pre-LSCs from genotoxic stress. We then used mice lacking the cell cycle regulator Cdkn1a (p21) to address the importance of quiescence in therapeutic resistance. Absence of p21 had no effect on the formation of pre-LSCs but reduced the proportion of quiescent pre-LSCs in vivo. Importantly, pre-LSCs lacking p21 were sensitive to killing by radiation therapy and chemotherapy. Finally, we aged cohorts of mice to determine the role of p21 in the clonal evolution of pre-LSCs. Remarkably, absence of p21 strongly impaired the clonal selection of pre-LSCs and the subsequent development of T-ALL. Gene expression analysis revealed that absence of p21 was associated with reduced expression of quiescence and increased expression of T-cell differentiation genes in pre-LSCs. The restored differentiation profile in Lmo2 mice lacking p21 together with these gene expression profiles indicate that loss of p21 triggers differentiation of pre-LSCs. These results provide the most convincing in vivo evidence that p21 is required for the quiescence, maintenance, clonal evolution and therapeutic resistance of pre-LSCs. Targeting p21 and other regulators of quiescence may represent a promising new therapeutic strategy for improving cure rates in T-ALL.",
author = "Cedric Tremblay and Saw, {Jesslyn Mei Yoong} and Chiu, {Sung Kai} and Curtis, {David John}",
year = "2015",
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note = "ISEH 44th Annual Scientific Meeting : International Society for Experimental Hematology, 44th Annual Scientific Meeting of the ISEH ; Conference date: 17-09-2015 Through 19-09-2015",
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Tremblay, C, Saw, JMY, Chiu, SK & Curtis, DJ 2015, 'Overcoming quiescence by targeting p21 (Cdkn1a) sensitizes pre-leukemic stem cells to chemotherapy' ISEH 44th Annual Scientific Meeting, Kyoto, Japan, 17/09/15 - 19/09/15, pp. S45.

Overcoming quiescence by targeting p21 (Cdkn1a) sensitizes pre-leukemic stem cells to chemotherapy. / Tremblay, Cedric; Saw, Jesslyn Mei Yoong; Chiu, Sung Kai; Curtis, David John.

2015. S45 Abstract from ISEH 44th Annual Scientific Meeting, Kyoto, Japan.

Research output: Contribution to conferenceAbstractOtherpeer-review

TY - CONF

T1 - Overcoming quiescence by targeting p21 (Cdkn1a) sensitizes pre-leukemic stem cells to chemotherapy

AU - Tremblay, Cedric

AU - Saw, Jesslyn Mei Yoong

AU - Chiu, Sung Kai

AU - Curtis, David John

PY - 2015/9/1

Y1 - 2015/9/1

N2 - T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous malignancy, with 1 out of 5 patients dying from refractory disease. Recent studies support the concept that cells responsible for relapse frequently develop from a small population of quiescent pre-leukemic stem cells (pre-LSCs) that give rise to clonal heterogeneity. Using the Lmo2 transgenic mouse model, we have shown previously that these pre-LSCs have long-term self-renewal potential and resistance to high dose radiation. To determine if quiescence is an important property of pre-LSCs, we first used the doxycycline inducible H2B-GFP transgenic mouse model to show the existence of rare (<1%) pre-LSCs that cycle less than once a month in Lmo2 transgenic mice. Importantly, radiation therapy lead to a 5-fold enrichment of these rare pre-LSCs, confirming that quiescence protects pre-LSCs from genotoxic stress. We then used mice lacking the cell cycle regulator Cdkn1a (p21) to address the importance of quiescence in therapeutic resistance. Absence of p21 had no effect on the formation of pre-LSCs but reduced the proportion of quiescent pre-LSCs in vivo. Importantly, pre-LSCs lacking p21 were sensitive to killing by radiation therapy and chemotherapy. Finally, we aged cohorts of mice to determine the role of p21 in the clonal evolution of pre-LSCs. Remarkably, absence of p21 strongly impaired the clonal selection of pre-LSCs and the subsequent development of T-ALL. Gene expression analysis revealed that absence of p21 was associated with reduced expression of quiescence and increased expression of T-cell differentiation genes in pre-LSCs. The restored differentiation profile in Lmo2 mice lacking p21 together with these gene expression profiles indicate that loss of p21 triggers differentiation of pre-LSCs. These results provide the most convincing in vivo evidence that p21 is required for the quiescence, maintenance, clonal evolution and therapeutic resistance of pre-LSCs. Targeting p21 and other regulators of quiescence may represent a promising new therapeutic strategy for improving cure rates in T-ALL.

AB - T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous malignancy, with 1 out of 5 patients dying from refractory disease. Recent studies support the concept that cells responsible for relapse frequently develop from a small population of quiescent pre-leukemic stem cells (pre-LSCs) that give rise to clonal heterogeneity. Using the Lmo2 transgenic mouse model, we have shown previously that these pre-LSCs have long-term self-renewal potential and resistance to high dose radiation. To determine if quiescence is an important property of pre-LSCs, we first used the doxycycline inducible H2B-GFP transgenic mouse model to show the existence of rare (<1%) pre-LSCs that cycle less than once a month in Lmo2 transgenic mice. Importantly, radiation therapy lead to a 5-fold enrichment of these rare pre-LSCs, confirming that quiescence protects pre-LSCs from genotoxic stress. We then used mice lacking the cell cycle regulator Cdkn1a (p21) to address the importance of quiescence in therapeutic resistance. Absence of p21 had no effect on the formation of pre-LSCs but reduced the proportion of quiescent pre-LSCs in vivo. Importantly, pre-LSCs lacking p21 were sensitive to killing by radiation therapy and chemotherapy. Finally, we aged cohorts of mice to determine the role of p21 in the clonal evolution of pre-LSCs. Remarkably, absence of p21 strongly impaired the clonal selection of pre-LSCs and the subsequent development of T-ALL. Gene expression analysis revealed that absence of p21 was associated with reduced expression of quiescence and increased expression of T-cell differentiation genes in pre-LSCs. The restored differentiation profile in Lmo2 mice lacking p21 together with these gene expression profiles indicate that loss of p21 triggers differentiation of pre-LSCs. These results provide the most convincing in vivo evidence that p21 is required for the quiescence, maintenance, clonal evolution and therapeutic resistance of pre-LSCs. Targeting p21 and other regulators of quiescence may represent a promising new therapeutic strategy for improving cure rates in T-ALL.

M3 - Abstract

SP - S45

ER -

Tremblay C, Saw JMY, Chiu SK, Curtis DJ. Overcoming quiescence by targeting p21 (Cdkn1a) sensitizes pre-leukemic stem cells to chemotherapy. 2015. Abstract from ISEH 44th Annual Scientific Meeting, Kyoto, Japan.