Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.

We previously demonstrated that severe hypoxia inhibits growth of Chronic Myeloid Leukemia (CML) cells and selects stem cells where BCR/Abl(protein) is suppressed, although mRNA is not, so that hypoxia-selected stem cells, while remaining leukemic, are independent of BCR/Abl signaling and thereby re...

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Autores principales:	Michele Tanturli, Serena Giuntoli, Valentina Barbetti, Elisabetta Rovida, Persio Dello Sbarba
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/26aef4698a424215bb706a55d7c289d4
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spelling	oai:doaj.org-article:26aef4698a424215bb706a55d7c289d42021-11-18T06:58:53ZHypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.1932-620310.1371/journal.pone.0017008https://doaj.org/article/26aef4698a424215bb706a55d7c289d42011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21347297/?tool=EBIhttps://doaj.org/toc/1932-6203We previously demonstrated that severe hypoxia inhibits growth of Chronic Myeloid Leukemia (CML) cells and selects stem cells where BCR/Abl(protein) is suppressed, although mRNA is not, so that hypoxia-selected stem cells, while remaining leukemic, are independent of BCR/Abl signaling and thereby refractory to Imatinib-mesylate. The main target of this study was to address the effects of the proteasome inhibitor Bortezomib (BZ) on the maintenance of stem or progenitor cells in hypoxic primary cultures (LC1), by determining the capacity of LC1 cells to repopulate normoxic secondary cultures (LC2) and the kinetics of this repopulation. Unselected K562 cells from day-2 hypoxic LC1 repopulated LC2 with rapid, progenitor-type kinetics; this repopulation was suppressed by BZ addition to LC1 at time 0, but completely resistant to day-1 BZ, indicating that progenitors require some time to adapt to stand hypoxia. K562 cells selected in hypoxic day-7 LC1 repopulated LC2 with stem-type kinetics, which was largely resistant to BZ added at either time 0 or day 1, indicating that hypoxia-selectable stem cells are BZ-resistant per se, i.e. before their selection. Furthermore, these cells were completely resistant to day-6 BZ, i.e. after selection. On the other hand, hypoxia-selected stem cells from CD34-positive cells of blast-crisis CML patients appeared completely resistant to either time-0 or day-1 BZ. To exploit in vitro the capacity of CML cells to adapt to hypoxia enabled to detect a subset of BZ-resistant leukemia stem cells, a finding of particular relevance in light of the fact that our experimental system mimics the physiologically hypoxic environment of bone marrow niches where leukemia stem cells most likely home and sustain minimal residual disease in vivo. This suggests the use of BZ as an enhanced strategy to control CML. in particular to prevent relapse of disease, to be considered with caution and to need further deepening.Michele TanturliSerena GiuntoliValentina BarbettiElisabetta RovidaPersio Dello SbarbaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 2, p e17008 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michele Tanturli Serena Giuntoli Valentina Barbetti Elisabetta Rovida Persio Dello Sbarba Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.
description	We previously demonstrated that severe hypoxia inhibits growth of Chronic Myeloid Leukemia (CML) cells and selects stem cells where BCR/Abl(protein) is suppressed, although mRNA is not, so that hypoxia-selected stem cells, while remaining leukemic, are independent of BCR/Abl signaling and thereby refractory to Imatinib-mesylate. The main target of this study was to address the effects of the proteasome inhibitor Bortezomib (BZ) on the maintenance of stem or progenitor cells in hypoxic primary cultures (LC1), by determining the capacity of LC1 cells to repopulate normoxic secondary cultures (LC2) and the kinetics of this repopulation. Unselected K562 cells from day-2 hypoxic LC1 repopulated LC2 with rapid, progenitor-type kinetics; this repopulation was suppressed by BZ addition to LC1 at time 0, but completely resistant to day-1 BZ, indicating that progenitors require some time to adapt to stand hypoxia. K562 cells selected in hypoxic day-7 LC1 repopulated LC2 with stem-type kinetics, which was largely resistant to BZ added at either time 0 or day 1, indicating that hypoxia-selectable stem cells are BZ-resistant per se, i.e. before their selection. Furthermore, these cells were completely resistant to day-6 BZ, i.e. after selection. On the other hand, hypoxia-selected stem cells from CD34-positive cells of blast-crisis CML patients appeared completely resistant to either time-0 or day-1 BZ. To exploit in vitro the capacity of CML cells to adapt to hypoxia enabled to detect a subset of BZ-resistant leukemia stem cells, a finding of particular relevance in light of the fact that our experimental system mimics the physiologically hypoxic environment of bone marrow niches where leukemia stem cells most likely home and sustain minimal residual disease in vivo. This suggests the use of BZ as an enhanced strategy to control CML. in particular to prevent relapse of disease, to be considered with caution and to need further deepening.
format	article
author	Michele Tanturli Serena Giuntoli Valentina Barbetti Elisabetta Rovida Persio Dello Sbarba
author_facet	Michele Tanturli Serena Giuntoli Valentina Barbetti Elisabetta Rovida Persio Dello Sbarba
author_sort	Michele Tanturli
title	Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.
title_short	Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.
title_full	Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.
title_fullStr	Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.
title_full_unstemmed	Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.
title_sort	hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/26aef4698a424215bb706a55d7c289d4
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Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.

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