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- Title
Glutamine Availability Controls BCR/Abl Protein Expression and Functional Phenotype of Chronic Myeloid Leukemia Cells Endowed with Stem/Progenitor Cell Potential.
- Authors
Poteti, Martina; Menegazzi, Giulio; Peppicelli, Silvia; Tusa, Ignazia; Cheloni, Giulia; Silvano, Angela; Mancini, Caterina; Biagioni, Alessio; Tubita, Alessandro; Mazure, Nathalie M.; Lulli, Matteo; Rovida, Elisabetta; Dello Sbarba, Persio
- Abstract
Simple Summary: In chronic myeloid leukemia (CML), a neoplasm brilliantly taken care of by a molecularly targeted therapeutic approach, the achievement of cure is nevertheless prevented by the maintenance of a small subset of treatment-resistant leukemia stem cells (LSCs), sustaining the so-called minimal residual disease of CML. The phenotypical and functional characterization of this LSC subset is, therefore, crucial to aim at the eradication of disease. Such a characterization includes the acquisition of information relative to the metabolic profile of treatment-resistant LSCs, which is functional to their maintenance in bone marrow. A number of metabolic features of LSCs were shown to determine their sensitivity or resistance to therapy. Glutamine metabolism emerged from this study as a potential target to overcome the persistence of therapy-resistant LSCs. This study was directed to characterize the role of glutamine in the modulation of the response of chronic myeloid leukemia (CML) cells to low oxygen, a main condition of hematopoietic stem cell niches of bone marrow. Cells were incubated in atmosphere at 0.2% oxygen in the absence or the presence of glutamine. The absence of glutamine markedly delayed glucose consumption, which had previously been shown to drive the suppression of BCR/Abl oncoprotein (but not of the fusion oncogene BCR/abl) in low oxygen. Glutamine availability thus emerged as a key regulator of the balance between the pools of BCR/Abl protein-expressing and -negative CML cells endowed with stem/progenitor cell potential and capable to stand extremely low oxygen. These findings were confirmed by the effects of the inhibitors of glucose or glutamine metabolism. The BCR/Abl-negative cell phenotype is the best candidate to sustain the treatment-resistant minimal residual disease (MRD) of CML because these cells are devoid of the molecular target of the BCR/Abl-active tyrosine kinase inhibitors (TKi) used for CML therapy. Therefore, the treatments capable of interfering with glutamine action may result in the reduction in the BCR/Abl-negative cell subset sustaining MRD and in the concomitant rescue of the TKi sensitivity of CML stem cell potential. The data obtained with glutaminase inhibitors seem to confirm this perspective.
- Subjects
GLUTAMINE metabolism; CHRONIC myeloid leukemia; GENE expression; TREATMENT effectiveness; CANCER patients; STEM cells; DESCRIPTIVE statistics; HEMATOPOIETIC stem cells; PHENOTYPES; DRUG resistance in cancer cells
- Publication
Cancers, 2021, Vol 13, Issue 17, p4372
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers13174372