Background: Incubation under severe hypoxia of CML cell lines selects hypoxiaresistant BCR/Abl-independent Leukaemia Stem Cells (LSC) and suppresses clonogenic progenitors (LPC). Hypoxia-selected LSC exhibited “primary” resistance to imatinibmesylate (IM), a feature highly relevant to the estabilishment of Minimal Residual Disease. Methods: Hypoxic (0.3% O2) CML cultures established with different cell densities and glucose concentrations were treated or not with IM. BCR/Abl expression was assessed by western blotting and BCR/abl transcription by RT-PCR. Stem cell potential was determined by the Culture-Repopulating Ability (CRA) assay. Results: The refractoriness of CML LSC/LPC to IM was explored in relation to their resistance to hypoxia or its combination with glucose shortage. It was possible to identify three hypoxia-resistant LSC/LPC subsets with different kinetic properties and IMresistance. Glucose availability in hypoxia appeared to regulate LSC/LPC balance; In fact, hypoxia-resistant cells maintained BCR/Ablprotein expression until glucose was available. LPC surviving merely hypoxic conditions were immediately recruitable to clonal expansion upon transfer to growth-permissive secondary cultures in normoxia. Such a property, due to the prompt rescue of BCR/Abl signaling was paralleled by LPC sensitivity to IM. LSC selected under hypoxia/ischemia were instead capable of delayed clonal expansion only and refractory to IM. IM-resistant LSC were also selected in hypoxia/ischemia from primary BCR/Abl-positive leukemia cells. Conclusions: This study evidenced the existence of hypoxia-resistant, BCR/Ablprotein– positive LPC sensitive to IM, as well as of ischemia-selected, BCR/Ablprotein–negative LSC refractory to IM. These LSC are suitable to home in vivo within hypoxic stem cell niches and to represent the CML cell subset responsible for MRD.

Glucose Availability in Hypoxia Regulates the Selection of CML Progenitor Subsets with Different Resistance to Imatinib-Mesylate / S. Giuntoli; M. Tanturli; F. Di Gesualdo; V. Barbetti; E. Rovida; P. Dello Sbarba. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - STAMPA. - 177:(2010), pp. s29-s30.

Glucose Availability in Hypoxia Regulates the Selection of CML Progenitor Subsets with Different Resistance to Imatinib-Mesylate

TANTURLI, MICHELE;DI GESUALDO, FEDERICO;ROVIDA, ELISABETTA;DELLO SBARBA, PERSIO
2010

Abstract

Background: Incubation under severe hypoxia of CML cell lines selects hypoxiaresistant BCR/Abl-independent Leukaemia Stem Cells (LSC) and suppresses clonogenic progenitors (LPC). Hypoxia-selected LSC exhibited “primary” resistance to imatinibmesylate (IM), a feature highly relevant to the estabilishment of Minimal Residual Disease. Methods: Hypoxic (0.3% O2) CML cultures established with different cell densities and glucose concentrations were treated or not with IM. BCR/Abl expression was assessed by western blotting and BCR/abl transcription by RT-PCR. Stem cell potential was determined by the Culture-Repopulating Ability (CRA) assay. Results: The refractoriness of CML LSC/LPC to IM was explored in relation to their resistance to hypoxia or its combination with glucose shortage. It was possible to identify three hypoxia-resistant LSC/LPC subsets with different kinetic properties and IMresistance. Glucose availability in hypoxia appeared to regulate LSC/LPC balance; In fact, hypoxia-resistant cells maintained BCR/Ablprotein expression until glucose was available. LPC surviving merely hypoxic conditions were immediately recruitable to clonal expansion upon transfer to growth-permissive secondary cultures in normoxia. Such a property, due to the prompt rescue of BCR/Abl signaling was paralleled by LPC sensitivity to IM. LSC selected under hypoxia/ischemia were instead capable of delayed clonal expansion only and refractory to IM. IM-resistant LSC were also selected in hypoxia/ischemia from primary BCR/Abl-positive leukemia cells. Conclusions: This study evidenced the existence of hypoxia-resistant, BCR/Ablprotein– positive LPC sensitive to IM, as well as of ischemia-selected, BCR/Ablprotein–negative LSC refractory to IM. These LSC are suitable to home in vivo within hypoxic stem cell niches and to represent the CML cell subset responsible for MRD.
2010
S. Giuntoli; M. Tanturli; F. Di Gesualdo; V. Barbetti; E. Rovida; P. Dello Sbarba
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/780426
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