Journal
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
Volume 96, Issue 2, Pages 204-212Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2010.029082
Keywords
imatinib-mesylate; chronic myeloid leukemia; glucose; hypoxia
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Funding
- Istituto Toscano Tumori (ITT)
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG5220]
- Associazione Italiana per la lotta contro le Leucemie e i Linfomi (AIL)
- Fondazione Cassa di Risparmio di Volterra
- Federazione Italiana per la Ricerca sul Cancro (FIRC)
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Background Incubation of chronic myeloid leukemia cells in hypoxia inhibits growth and selects BCR/Abl-independent cells with stem cell properties which are refractory to imatinib-mesylate. This study aimed to characterize the relationship of this refractoriness with glucose availability in the environment. Design and Methods K562 or primary chronic myeloid leukemia cells were cultured at 0.1% O-2, different cell densities and glucose concentrations. The stem and progenitor cell potential of these cultures at different times of incubation in relation to BCR/Abl(protein) expression and sensitivity to imatinib-mesylate was explored by transferring cells to growth-permissive secondary cultures in normoxia, according to the Culture-Repopulating Ability assay methodology. Results Hypoxia-resistant cells maintained BCR/Abl(protein) expression until glucose was no longer available in primary hypoxic cultures, where glucose availability appeared to regulate cell number and the balance between the enrichment, of cells with kinetic properties typical of stem or progenitor cells. Cells surviving merely hypoxic conditions were, upon transfer to secondary cultures, immediately available for numerical expansion due to the maintained BCR/Abl(protein) expression, and were consequently sensitive to imatinib-mesylate. Instead, BCR/Abl(protein) negative cells selected in primary cultures under oxygen/glucose shortage underwent a delayed numerical expansion in secondary cultures, which was completely refractory to imatinib-mesylate. Cells with the latter properties were also found in primary chronic myeloid leukemia explants. Conclusions Glucose shortage in hypoxia was shown to represent the condition selecting BCR/Abl(protein)-negative cells refractory to imatinib-mesylate from either chronic myeloid leukemia lines or patients. These cells, exhibiting stem cell properties in vitro, are metabolically suited to home to stem cell niches in vivo and so may represent the chronic myeloid leukemia cell subset responsible for minimal residual disease.
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